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318 Models

Name Other Names Strain Name Genetic Background Gene Mutation Modification Info Modification Disease Neuropathology Behavior/Cognition Other Phenotype Availability Primary Paper Visualization
Mouse Models (293)
<p>-</p>, <p>3xTg-AD</p>, <p>The LaFerla mouse</p> B6;129-Psen1tm1Mpm Tg(APPSwe,tauP301L)1Lfa/Mmjax C7BL/6;129X1/SvJ;129S1/Sv Psen1, APP, MAPT APP K670_M671delinsNL (Swedish), MAPT P301L, PSEN1 M146V Single-cell embryos from mice with knock-in of PSEN1 with the PS1M146V mutation were injected with two human transgenes (APP with the Swedish mutation and MAPT with the P30IL mutation). Transgenes integrated at a single locus under the control of the mouse Thy1.2 promoter. Psen1: Knock-In; APP: Transgenic; MAPT: Transgenic Alzheimer's Disease Age-related, progressive neuropathology including plaques and tangles. Extracellular Aβ deposits by 6 months in frontal cortex, more extensive by 12 months. No tau pathology at 6 months, but evident at 12 months. Synaptic dysfunction, including LTP deficits, prior to plaques and tangles. Cognitive impairment by 4 months. Impairments first manifest as a retention/retrieval deficit and not as a learning deficit, and occur prior to plaques and tangles. Deficits in both spatial and contextual based paradigms. Clearance of intraneuronal Aβ by immunotherapy rescues the early cognitive deficits in a hippocampal-dependent task. The Jackson Lab; available through the JAX MMRRC Stock# 034830; Live Oddo et al., 2003 Yes
<p>-</p>, <p>5XFAD</p>, <p>APP/PS1</p>, <p>Tg6799</p>, <p>Tg-5xFAD</p> B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax C57BL/6 x SJL APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V Two transgenes: mutant human APP with the APP Swedish, Florida, and London mutations and containing the 5' untranslated region driven by the mouse Thy1 promoter; and mutant human PSEN1 including the M146L and L286V mutations driven by the mouse Thy1 promoter. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid pathology starting at 2 months, including amyloid plaques. Accumulation of intraneuronal Aβ before amyloid deposition. Gliosis and synapse degeneration. Neuron loss in cortical layer 5 and subiculum. No neurofibrillary tangles. Age-dependent memory deficits including spatial memory, stress-related memory, and memory stablization. Motor phenotype. The Jackson Lab; available through the JAX MMRRC Stock# 034840; Live. Oakley et al., 2006 Yes
<p>-</p>, <p>5XFAD</p>, <p>APP/PS1</p>, <p>Tg6799</p>, <p>Tg-5xFAD</p> B6.Cg-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax C57BL6 APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V Two transgenes: mutant human APP with the APP Swedish, Florida, and London mutations and containing the 5' untranslated region driven by the mouse Thy1 promoter; and mutant human PSEN1 including the M146L and L286V mutations driven by the mouse Thy1 promoter. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid pathology starting at 2 months, including amyloid plaques. Accumulation of intraneuronal Aβ before amyloid deposition. Gliosis and synapse degeneration. Neuron loss in cortical layer V. Age-dependent memory deficits, motor phenotype, and reduced anxiety. Available from The Jackson Laboratory, JAX MMRRC Stock# 034848. Research with this model is available from Scantox Neuro. Jawhar et al., 2012, Richard et al., 2015 Yes
C57BL/6J APP APP K670_M671delinsNL (Swedish), APP T714I (Austrian) Transgene-expressing mutant APP with the Swedish mutation (K670N/M671L) and the Austrian mutation (T714I) under the control of the Thy1.2 promoter. APP: Transgenic Alzheimer's Disease Progressive amyloid deposition in the cerebral cortex by approximately 9-12 months. Unknown. Optogenetic stimulation induced epileptic seizures. Unknown Yamada et al., 2009 Yes
<p>-</p>, <p>GFP-(GA)<sub>50</sub></p> C57BL/6J An adeno-associated viral (AAV) vector encoding 50 glycine-alanine (GA) repeats tagged with green fluorescent protein was injected into the ventricles of neonatal mice. Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Poly(GA)- and ubiquitin-positive inclusions in neurons are primarily cytoplasmic and also co-localize with HR23A and HR23B proteins and the nuclear pore complex proteins RanGAP1 and Pom121. Neuron loss and astrogliosis in cortex and hippocampus. Motor deficits, impaired coordination, hyperactivity, increased anxiety, and deficits in contextual and cued fear conditioning. Viral construct available through Leonard Petrucelli. Zhang et al., 2016 Yes
<p>-</p>, <p>GFP–(GR)<sub>100</sub></p> C57BL/6J An adeno-associated viral (AAV) vector encoding 100 glycine-arginine (GR) repeats tagged with green fluorescent protein was injected into the ventricles of neonatal mice. Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Progressive neuron loss in cortex and hippocampus, gliosis. Lacks poly(GR) inclusions. Rare TDP-43 inclusions. Progressive motor deficits and age-dependent cognitive impairment. Viral construct available through Leonard Petrucelli. Zhang et al., 2018 Yes
<p>-</p>, <p>5xFAD-sTREM2</p> 5xFAD (C57BL6) TREM2, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V Adeno-associated viruses (AAV2/8) expressing EGFP- and FLAG-tagged human TREM2 (amino acids 1-171) under the control of the CAG promoter were injected bilaterally into the lateral ventricles of neonatal 5xFAD mice. TREM2: Virus; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease AAV-mediated over expression of sTREM2 decreased amyloid plaque burdens and increased numbers of plaque-associated microglia in the brains of 5xFAD mice. 5xFAD mice show impaired learning and memory in the Morris water maze, but AAV-sTREM2 5xFAD mice performed as well as non-transgenic controls. Long-term potentiation at Shaeffer collateral-CA1 synapses is impaired in 5xFAD mice. AAV-mediated over expression of sTREM2 rescued LTP in AAV-sTREM2 5xFAD mice. 5xFAD mice are available from The Jackson Laboratory, JAX MMRRC Stock# 034848. Research with 5xFAD is available from Scantox Neuro. Zhong et al., 2019 Yes
<p>-</p>, <p>AAV-sTREM2 Tau P301S</p> Tau P301S (Line PS19) TREM2, MAPT MAPT P301S Adeno-associated viruses (AAV2/8) expressing EGFP- and FLAG-tagged human TREM2 (amino acids 1-171) under the control of the CAG promoter were injected bilaterally into the hippocampi of 3-month-old male PS19 mice. Control mice received injections of AAV expressing only EGFP. TREM2: Virus; MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease AAV-mediated expression of sTREM2 protected against hippocampal synapse loss in PS19 mice. AAV-mediated expression of sTREM2 improved performance of PS19 mice in the Morris water maze and Y-maze. Levels of p-tau202 and p-tau396 and activity of GSK3β were lower in AAV-sTREM2 PS19 mice compared with PS19 mice who received control vector. PS19 mice are available from The Jackson Lab: Stock# 008169; Live. Research with PS19 mice is available from Scantox Neuro. Zhang et al., 2023 Yes
B6.Cg-Apoetm1.1(APOE*4)Adiuj Abca7em#2Adiuj Trem2em1Adiuj/J C57BL/6J Abca7, APOE, Trem2 TREM2 R47H CRISPR/Cas9 was used to introduce the rs3752246 SNP mutation (p.A1527G) into the Abca7 gene of double mutant mice with a humanized APOE4 gene and the R47H point mutation knocked into the mouse Trem2 gene (B6(SJL)-Apoetm1.1(APOE*4)Adiuj Trem2em1Adiuj/J, The Jackson Laboratory Stock# 028709). Abca7: Knock-In; APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease Unknown. Unknown. The Jackson Laboratory, Stock# 030283. Cryopreserved. The Jackson Laboratory Yes
B6.Cg-Apoetm1.1(APOE*4)Adiuj Abca7em#1Adiuj Trem2em1Adiuj/J C57BL/6J Abca7, APOE, Trem2 TREM2 R47H CRISPR/cas9 was used to generate a knock-out mutation of the Abca7 gene of double mutant mice with a humanized APOE4 gene and the p.R47H point mutation knocked into the mouse Trem2 gene (B6(SJL)-Apoetm1.1(APOE*4)Adiuj Trem2em1Adiuj/J, The Jackson Laboratory Stock# 028709). Abca7: Knock-Out; APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease Unknown. Unknown. The Jackson Laboratory, Stock# 030320. Cryopreserved. The Jackson Laboratory Yes
<p>-</p>, <p>Dan-amyloid</p>, <p>BRI2-Danish</p>, <p>ADan precursor protein</p> Tg(Prnp-ITM2B*)6Jckr and Tg(Prnp-ITM2B*)7Jckr C57BL/6J ITM2B (BRI2) BRI2: Familial Danish Dementia (FDD) duplication Transgenic mice with human BRI2 gene containing the Familial Danish Dementia (FDD) mutation under the control of the Syrian hamster prion protein promoter. The FDD mutation is a 10-nucleotide duplication in the region of the stop codon in the BRI2 gene, resulting in a C-terminally elongated protein. ITM2B (BRI2): Transgenic Familial Danish Dementia, Alzheimer's Disease, Cerebral Amyloid Angiopathy ADan deposition starts in the hippocampus and meningeal vessels at 2 months and increases with age. By 18 months, deposition is widespread. The majority of amyloid deposits are associated with the vasculature, where they destroy the integrity of the vessel wall and lead to microhemorrhages. Parenchymal amyloid plaques surrounded by microglia and dystrophic neurites are also present. Impaired performance in Morris water maze, due to a combination of both motor deficits (i.e. reduced swim speed) and spatial learning deficits reported at 18-20 months. Open field test at 18-20 months also showed an anxiety-related phenotype. Adult mice fail to gain weight with age. Alopecia. Kyphosis. Available through Mathias Jucker Coomaraswamy et al., 2010 Yes
<p>-</p>, <p>5xFAD BxD</p> (B6.Cg-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax x BXD[strain number] C57BL/6J X BXD[strain number] APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V “AD-BXD” refers to a panel of transgenic mouse strains, created by crossing 5XFAD mice to members of the BXD genetic reference panel. 5XFAD mice carry APP (with the Swedish, Florida, and London mutations) and PSEN1 (with M146L and L286V mutations) transgenes. The BXD genetic reference panel is a set of recombinant inbred mouse strains derived from crossing the C57BL/6J and DBA/2J inbred strains. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Transgenic AD-BXD mice develop amyloid plaques by 6 months of age, although the extent of plaque deposition is strain-dependent. Transgenic AD-BXD mice exhibit cognitive deficits, assessed using contextual fear conditioning. The age of onset and severity of impairment are strain-dependent. Individual AD-BXD strains are available as F1 hybrids from The Jackson Laboratory (each strain has its own stock number). Neuner et al., 2019 Yes
<p>-</p>, <p>Amyloid β (A4) precursor-like protein 2 knock-out</p>, <p>APLP2 KO</p> B6.129S7-Aplp2tm1Dbo/J 129S7,C57BL/6J; backcrossed to C57BL/6J Aplp2 Inactivation of the mouse APLP2 gene by deleting a 1.1kb region containing the promoter and exon 1 using a targeting vector containing a PGK-neomycin expression cassette for positive selection and a MC1-TK cassette for negative selection. Aplp2: Knock-Out Alzheimer's Disease Not observed. Not observed. Homozygous animals are viable, normal in size, fertile, and do not display any gross physical or behavioral abnormalities up to 22 months of age. No impairments in axonal outgrowth of olfactory neurons following bulbectomy. The Jackson Lab: Stock# 004142; Cryopreserved von Koch et al., 1997 No
APOE2 KI C57BL/6; 129P2, backcrossed to C57BL/6J APOE The human APOE2 cDNA sequence was knocked-in at the endogenous mouse APOE locus; inserted in frame with non-coding sequences, exon 1, intron 1 and the first 18 bp of exon 2 such that expression is regulated by endogenous regulatory elements and the mouse APOE gene inactivated. APOE: Knock-In Alzheimer's Disease, Traumatic Brain Injury Unknown. Unknown. 2-fold higher level of steady state APOE in brain and higher APOE in serum compared with APOE3 and APOE4 KI animals. Highest levels of serum cholesterol and triglycerides after a 6hr fast. No longer available through Bruce Lamb Mann et al., 2004 No
<p>-</p>, <p>E2F</p> C57BL/6J APOE The coding region of the mouse Apoe gene, from the translation initiation codon in exon 2 to the termination codon in exon 4, was replaced with the corresponding human APOE (ε2 allele) sequence, flanked by loxP sites. APOE: Knock-In Alzheimer's Disease Unknown. Unknown. Available through a material transfer agreement with the Cure Alzheimer’s Fund. Huynh et al., 2019 Yes
<p>-</p>, <p>APOE2 KI</p>, <p>APOE*2 KI</p> B6.Cg-Apoeem3(APOE*)Adiuj/J C57BL/6J APOE APOE2 KI mice were generated by using CRISPR/Cas9 to introduce two point mutations (leading to arginine to cysteine substitutions at amino acids 130 and 176) in an existing humanized APOE4 knock-in allele (The Jackson Laboratory Stock# 027894). APOE: Knock-In Alzheimer's Disease Unknown. Unknown. The Jackson Laboratory, Stock# 029017. Live. The Jackson Laboratory Yes
<p>-</p>, <p>APOE2 Humanized Knock-in</p> B6.129P2-Apoetm1(APOE*2)Mae N9 129 x C57BL/6; back-crossed to C57BL/6 APOE APOE R176C (ApoE2) Targeted gene replacement of the endogenous murine APOE gene with the human APOE2 allele. Targeting construct included exons 2-4 of APOE2. APOE: Knock-In Alzheimer's Disease, Multiple Conditions None reported. White-matter integrity, as assessed by fractional anisotropy, was reported to be higher in the hippocampus and caudate putamen of year-old female APOE2 mice, compared with APOE3 females; these genotype differences were not seen in males. Findings are mixed, with some studies reporting that APOE genotype—in some cases, interacting with sex or age—affects performance in behavioral assays. Characteristics of type III hyperlipoproteinemia. Plasma cholesterol and triglyceride levels 2-3x higher than APOE3 mice. Impaired clearance of very-low-density lipoprotein (VLDL) particles. Atherosclerotic plaques. Compared with APOE3 mice, APOE2 mice exhibited higher levels of glucose uptake in the cortex and hippocampus and up-regulation of genes involved in glucose utilization. Taconic: Stock# 1547-F and 1547-M Sullivan et al., 1998 No
<p>-</p>, <p>E3F</p> C57BL/6J APOE The coding region of the mouse Apoe gene, from the translation initiation codon in exon 2 to the termination codon in exon 4, was replaced with the corresponding human APOE (ε3 allele) sequence, flanked by loxP sites. APOE: Knock-In Alzheimer's Disease Unknown. Unknown. Available through a material transfer agreement with the Cure Alzheimer’s Fund. Huynh et al., 2019 Yes
<p>-</p>, <p>APOE3 KI</p>, <p>APOE*3 KI</p> B6(SJL)-ApoEem2(APOE*)Adiuj/J C57BL/6J APOE CRISPR/Cas9 used to introduce a point mutation (leading to an arginine-to-cysteine substitution at amino acid 130) into an existing humanized APOE4 knock-in allele. APOE: Knock-In Alzheimer's Disease No data. No data. The Jackson Laboratory, Stock # 029018; Live The Jackson Laboratory Yes
<p>-</p>, <p>APOE3 KI</p> C57BL/6; 129P2, backcrossed to C57BL/6J APOE The human APOE3 cDNA sequence was knocked-in at the endogenous mouse APOE locus; inserted in frame with non-coding sequences, exon 1, intron 1 and the first 18bp of exon 2 such that expression is regulated by endogenous regulatory elements and the mouse APOE gene inactivated. APOE: Knock-In Alzheimer's Disease, Traumatic Brain Injury Unknown. Unknown. Intermediate brain APOE and serum cholesterol levels compared with mice with knock-in of APOE4 or APOE2. No longer available through Bruce Lamb Mann et al., 2004 Yes
<p>-</p>, <p>APOE3 Humanized Knock-in</p> B6.129P2-Apoetm2(APOE*3)Mae N8 129 x C57BL/6; back-crossed to C57BL/6 APOE Targeted replacement of the endogenous mouse APOE gene with the human APOE3 allele. Targeting vector contained exons 2-4 of human APOE3. APOE: Knock-In Alzheimer's Disease, Multiple Conditions None reported. APOE3 was considered the neutral allele against which the other human APOE genotypes were compared in most studies of neurological phenotypes in Targeted Replacement mice. Data comparing Targeted Replacement mice to wild-type mice are limited. Findings are mixed, with some studies reporting that APOE genotype—in some cases, interacting with sex or age—affects performance in behavioral assays. On a standard diet, homozygous mice have normal cholesterol and triglyceride levels, but are more susceptible than wild-type animals to diet-induced atherosclerosis. Data comparing neurological phenotypes in Targeted Replacement mice to wild-type mice are sparse, but APOE3 mice resemble wild-type mice with respect to aspects of hippocampal anatomy and physiology, including LTP and neurogenesis. Taconic: Stock# 1548-F and 1548-M Sullivan et al., 1997 No
<p>-</p>, <p>E4F</p> C57BL/6J APOE The coding region of the mouse Apoe gene, from the translation initiation codon in exon 2 to the termination codon in exon 4, was replaced with the corresponding human APOE (ε4 allele) sequence, flanked by loxP sites. APOE: Knock-In Alzheimer's Disease Unknown. Unknown. Available through a material transfer agreement with the Cure Alzheimer’s Fund. Huynh et al., 2019 Yes
<p>-</p>, <p>APOE4 KI</p>, <p>APOE*4 KI</p> B6(SJL)-ApoEtm1.1(APOE*4)Adiuj/J C57BL/6J APOE Mouse ApoE exons 2, 3, and most of exon 4 replaced with human APOE sequence including exons 2, 3, 4 and a portion of the 3' UTR sequence. APOE: Knock-In Alzheimer's Disease No data. No data. The Jackson Laboratory, Stock # 027894; Live The Jackson Laboratory Yes
APOE4 KI C57BL/6; 129P2, backcrossed to C57BL/6J APOE The human APOE4 cDNA sequence was knocked-in at the endogenous mouse APOE locus; inserted in frame with non-coding sequences, exon 1, intron 1 and the first 18 bp of exon 2 such that expression is regulated by endogenous regulatory elements and the mouse APOE gene inactivated. APOE: Knock-In Alzheimer's Disease, Traumatic Brain Injury Unknown. Unknown. Human ApoE is detectable in serum and astrocytes. Compared to mice with knock-in of APOE2 or APOE3, APOE4 mice had the lowest serum cholesterol after a 6 hour fast. No longer available through Bruce Lamb Mann et al., 2004 No
<p>-</p>, <p>APOE4 Humanized Knock-in</p> B6.129P2-Apoetm3(APOE*4)Mae N8 129 x C57BL/6, back-crossed to C57BL/6 APOE APOE C130R (ApoE4) Targeted replacement of the endogenous murine APOE gene with the human APOE4 allele; targeting construct contained exons 2–4 of APOE4. APOE: Knock-In Alzheimer's Disease, Multiple Conditions Mice do not develop amyloid plaques or neurofibrillary tangles. Genotype-dependent differences in brain structure have been reported, but findings are mixed. While some groups have found smaller hippocampal volumes, enlarged ventricles, and compromised white matter in APOE4 mice compared with APOE3, others did not observe these differences. Findings are mixed, with some studies reporting that APOE genotype—in some cases, interacting with sex or age—affects performance in behavioral assays. Increased risk of atherosclerosis. Elevated cholesterol, APOE, and APOB-48 on a high fat diet. Transcriptomic and functional evidence for increased aerobic glycolysis and decreased mitochondrial respiration in APOE4 compared with APOE3 mice. Electrophysiological and imaging studies suggest that aged APOE4 mice exhibit neural hyperactivity compared with APOE3 mice in some brain regions. Taconic: Stock# 1549-F or 1549-M Knouff et al., 1999 No
<p>-</p>, <p>APOE KO</p>, <p>APOE -/-</p>, <p>APOE TM1</p> B6.129P2-Apoetm1Unc N11 129 x C57BL/6, back-crossed to C57BL/6 APOE Inactivation of the endogenous mouse APOE by homologous recombination and insertion of a neomycin cassette. APOE: Knock-Out Alzheimer's Disease Unknown. Unknown. Viable; healthy. Undetectable ApoE protein in plasma. Plasma cholesterol 5x higher than wild-type. Artherosclerotic lesions which progress to occlusions of coronary artery by 8 months. Taconic: Stock# APOE-M and APOE-F Piedrahita et al., 1992 No
<p>-</p>, <p>B6-Tg/Thy1APP23Sdz</p> B6.Cg-Tg(Thy1-APP)3Somm/J C57BL/6 APP APP K670_M671delinsNL (Swedish) Transgene containing human APP (isoform 751) containing the Swedish (KM670/671NL) mutation under the murine Thy1 promoter. APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy Aβ deposits first observed at 6 months. Congophilic plaques increase in size and number with age and are surrounded by activated microglia, astrocytes, and dystrophic neurites containing hyperphosphorylated tau (although no neurofibrillary tangles). Neuronal loss in the CA1 region of the hippocampus. Mice also develop CAA, and microhemorrages occur at later ages. Spatial memory defects in Morris Water maze at 3 months and progresses with age. Memory deficits in passive avoidance were observed in 25 month-old mice, but not at younger ages. Hyperactivity observed between the ages of 6 weeks to 6 months. It is not known whether this persists or resolves in older animals. Abnormalities in open field test and impaired performance on rotorod observed from 3 months. Available through The Jackson Laboratory Stock# 030504, Live Sturchler-Pierrat et al., 1997 Yes
B6.Cg-Tg(Thy1-APP)3Somm/J; Psen1tm1.1Tcs C57BL/6J APP, PSEN1 PSEN1 R278I This is a cross between APP23 mice, which overexpress APP751 with the Swedish mutation driven by the murine Thy1 promoter, and PSEN1 knock-in mice expressing human PSEN1 with the R278I mutation under the endogenous promoter. APP: Transgenic; PSEN1: Knock-In Alzheimer's Disease Amyloid deposition by 6 months of age in the cortex and hippocampus. Abundant reactive astrocytes in the vicinity of plaques. Elevated Aβ43 in the brain by 3 months. High density of cored plaques. Pyroglutamate Aβ (N3pE-Aβ) associated with amyloid plaques. Short-term memory deficits apparent by 3-4 months as measured by the Y maze. Reduced γ-secretase activity. Available through Takaomi Saido Saito et al., 2011 Yes
<p>-</p>, <p>APP(SL)PS1KI</p>, <p>APPxPS1-Ki</p>, <p>APPSL/PS1KI</p>, <p>APP(SL)/PS1(KI)</p>, <p>APP/PS1KI</p> The PS1KI line was established in 129SV and backcrossed &gt;7 times to C57BL/6 background. The PS1KI were bred with APPSL mice on a C57BL background (two rounds) to obtain a homozygote PS1KI and heterozygote APP. APP, PSEN1 APP K670_M671delinsNL (Swedish), APP V717I (London), PSEN1 M233T, PSEN1 L235P This animal is a cross between a PSEN1 knock-in line and an APP over-expressing line. The PS1 knock-in line was generated by introducing two point mutations in the wild-type mouse PSEN1, corresponding to the mutations M233T and L235P. APP751SL overexpresses human APP751 carrying the London (V717I) and Swedish (K670N/M671L) mutations under the control of the Thy1 promoter. APP: Transgenic; PSEN1: Knock-In Alzheimer's Disease Acceleration of extracellular Aβ deposition compared to the single transgenics. Age-dependent neuronal loss in the hippocampus with extensive neuronal loss in the CA1/2 at 10 months with detection as early as 6 months in female mice. Intraneuronal Aβ and thioflavin-S-positive deposits before neuronal loss. Astrogliosis in proximity of Aβ-positive neurons. Age-dependent impairments in working memory as measured by the Y maze and T-maze continuous alternation task. No deficit at 2 months, but deficits at 6 and 12 months compared to PS1KI littermates. Viable and fertile. 6 month-old animals develop decreases in body weight, and a spinal deformity (kyphosis) is common. Impaired neurogenesis. Available through Thomas Bayer or Benoit Delatour Casas et al., 2004 Yes
<p>tg13592</p> C57BL/6 x DBA/2 APP Transgene consisting of the signal plus 99-amino acid carboxyl-terminal sequence (SbC) of APP under the control of a cytomegalovirus enhancer/β-actin promoter. APP: Transgenic Alzheimer's Disease No neuropathology up to age 29 months; however, pathology reminiscent of inclusion body myopathy observed at 6-12 months: Aβ-immunoreactive deposits in skeletal muscle fibers. Muscle fibers with Aβ-immunoreactive deposits increased with age and also became vacuolated. Hypoactivity. The acquisition of place learning in the Morris water maze task was impaired. Higher cytochrome oxidase activity in thalamic nuclei. High levels of Aβ peptides in the plasma. Available through Ken-ichiro Fukuchi, University of Illinois College of Medicine at Peoria Fukuchi et al., 1996 No
<p>-</p>, <p>APP-Dutch</p>, <p>Tg-APP(Dutch)</p>, <p>APP E693Q</p>, <p>APP Dutch</p> C57BL/6J-Tg(Thy1-APPDutch)#Jckr C57BL/6J APP APP E693Q (Dutch) Transgenic mice with human APP751 bearing the E693Q mutation under the murine Thy1 promoter. APP: Transgenic Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type, Cerebral Amyloid Angiopathy, Alzheimer's Disease Increased Aβ40/42 ratio. Extensive vascular Aβ deposition starting at 22-24 months appearing first in leptomeningeal vessels followed by cortical vessels, leading to smooth muscle cell degeneration, hemorrhages, and neuroinflammation. Parenchymal amyloid plaques are not observed.  Unknown. Available through Mathias Jucker Herzig et al., 2004 Yes
<p>Osaka</p>, <p>APP(OSK)-Tg</p>, <p>APP Osaka mutation transgenic</p>, <p>APPOSK-Tg mice</p>, <p>APPOSK mice</p> B6C3F1, back-crossed to C57Bl/6 APP APP E693del (Osaka) Transgenic expression of human APP695 with the Osaka mutation driven by the mouse prion promoter. APP: Transgenic Alzheimer's Disease Age-dependent accumulation of Aβ oligomers within hippocampal and cortical neurons, but negligible deposits of extracellular amyloid. Abnormal tau phosphorylation, but no overt tangle pathology. Synaptic loss and gliosis in hippocampus and cerebral cortex. Late neuronal loss in the CA3 region of the hippocampus. Memory impairment by eight months as measured by the Morris water maze. Specifically, reduced spatial reference memory in the Morris water maze compared to mice expressing comparable levels of wild-type human APP. Available from TransGenic Inc. Tomiyama et al., 2010 Yes
<p>-</p>, <p>APP KI</p>, <p>line ADF</p> Apptm1Sud/J Strain of origin: (129X1/SvJ x 129S1/Sv)F1-Kitl&lt;+&gt;; C57BL/6 and maintained on a mixed background APP APP K670_M671delinsNL (Swedish), APP V717I (London), APP E693Q (Dutch) Knock-in of wild-type mouse APP exon 16 (truncated after residue KM), FLAG tag (2 repeats), a stop codon, a poly A signal region from the human growth hormone gene and an additional copy of exon 16 carrying the Swedish mutation and a modified exon 17 with the London and Dutch mutations. APP: Knock-In Alzheimer's Disease Unknown. Unknown. The Jackson Lab: Stock# 008390; Cryopreserved The Jackson Laboratory No
<p>-</p>, <p>App<sup>hu/hu</sup></p> Appem1Bdes C57BL6J App CRISPR/Cas9 was used to introduce the following mutations into the endogenous App gene: G676R (G5R), F681Y (F10Y), R684H (R13H), numbered according to the 770 amino-acid isoform of human APP (position within the Aβ sequence). App: Knock-In Alzheimer's Disease Unknown. Unknown. Levels of CTFβ and Aβ are elevated in the brains of these knock-in mice, compared with wild-type animals. Available through Lutgarde Serneels and The Mary Lyon Centre at MRC Harwell, Archive# HAR:010358. Serneels et al., 2020 Yes
<p>-</p>, <p>APP null</p>, <p>APP KO</p> B6.129S7-Apptm1Dbo/J C57BL/6J APP Inactivation of the mouse APP gene by replacing a 3.8 kb sequence encoding the promoter and exon 1 with a neomycin resistance cassette. APP: Knock-Out Alzheimer's Disease Elevated reactive gliosis by 14 weeks in the hippocampus and parts of the neocortex. Impaired spatial learning as measured by the water maze at 4 and 10 months. Hypoactivity and decreased locomotor activity and forelimb grip strength. Homozygous knock-out mice weigh 15-20% less than age-matched wild-type mice. The Jackson Lab: Stock# 004133; Live Zheng et al., 1995 No
B6.Cg-Apoetm1.1(APOE*4)Adiuj Appem2Adiuj Trem2em1Adiuj/J C57BL/6J APOE, App, Trem2 TREM2 R47H CRISPR/Cas9 was used to introduce a 94-bp deletion in exon 14 (APP695 numbering) of  the App gene of double mutant mice with a humanized APOE4 gene and the p.R47H point mutation knocked into the mouse Trem2 gene (The Jackson Laboratory Stock# 028709). APOE: Knock-In; App: Knock-Out; Trem2: Knock-In Alzheimer's Disease Unknown. Unknown. The Jackson Laboratory, Stock# 031722. Cryopreserved. The Jackson Laboratory Yes
<p>-</p>, <p>APP<sup>NL-F/NL-F</sup></p> Apptm2.1Tcs/Apptm2.1Tcs C57BL/6 APP APP K670_M671delinsNL (Swedish), APP I716F (Iberian) Knock-in of APP sequence including introns 15 to 17. Sequence was modified to contain a humanized Aβ region and the Swedish and Beyreuther/Iberian mutations. APP: Knock-In Alzheimer's Disease Elevated Aβ peptides accumulating into plaques starting at 6 months. Microgliosis and astrocytosis, especially around plaques. Reduced synaptophysin and PSD-95 indicative of synaptic loss. No tangle pathology or neurodegeneration. Memory impairment by 18 months as measured by the Y maze. No significant impairment in the Morris water maze. No overexpression of APP. Generates wild-type levels of AICD. Available through Takaomi Saido Saito et al., 2014 Yes
<p>-</p>, <p>APP<sup>NL-G-F/NL-G-F</sup></p>, <p>App<sup>NL-G-F</sup></p> Apptm3.1Tcs/Apptm3.1Tcs C57BL/6 APP APP K670_M671delinsNL (Swedish), APP I716F (Iberian), APP E693G (Arctic) Knock-in of APP sequence including introns 15 to 17. Sequence was modified to contain a humanized Aβ region and three pathogenic mutations (Swedish, Beyreuther/Iberian, and Arctic). APP: Knock-In Alzheimer's Disease Aggressive amyloidosis with deposition in the cortex beginning at 2 months and approaching saturation by 7 months. Aβ deposition in heterozygous mice at 4 months. Subcortical amyloidosis. Exacerbated microgliosis and astrocytosis compared to APPNL-F mice. Reduced synaptophysin and PSD-95 indicative of synaptic loss. No tangle pathology or neurodegeneration. Memory impairment by 6 months as measured by the Y maze. No overexpression of APP. Wild-type levels of AICD. Available through Takaomi Saido Saito et al., 2014 Yes
<p>-</p>, <p>App<sup>NL-G-F</sup>/MAPT double knock-in</p>, <p>App<sup>NL-G-F</sup>/MAPT dKI</p> C57BL/6J App, MAPT APP K670_M671delinsNL (Swedish), APP I716F (Iberian), APP E693G (Arctic) AppNL-G-F mice (mouse App sequence modified to contain a humanized Aβ region and the Swedish, Iberian, and Arctic mutations linked to AD) were crossed with MAPT knock-in mice (entire genomic sequence of murine Mapt, from exon 1 to exon 14, replaced with the human MAPT gene from the ATG codon of exon 1 to the 3'-untranslated region). App: Knock-In; MAPT: Knock-In Alzheimer's Disease Amyloid plaques, plaque-associated neuritic dystrophy, and neuroinflammation, similar to AppNL-G-F. Deficits in the Y-maze test of working memory, similar to AppNL-G-F. Compared with AppNL-G-F mice, AppNL-G-F/MAPT double knock-in mice showed accelerated propagation of pathological tau species after AD-derived tau was injected into the mouse brain. Available through Takaomi Saido, RIKEN Center for Brain Science. Saito et al., 2019, Hashimoto et al., 2019 Yes
<p>-</p>, <p>APPPS1-21</p>, <p>APP/PS1</p> B6.Cg-Tg(Thy1-APPSw,Thy1-PSEN1*L166P)21Jckr C57BL/6J APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1 L166P Human transgenes APP KM670/671NL and PSEN1 L166P, both under the control of the Thy1 promoter. Integration site is on lower arm of chromosome 2 between 40 and 60 cm. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaque deposition starts at approximately 6 weeks in the neocortex. Amyloid deposits in the hippocampus appear at 3-4 months, and in the striatum, thalamus and brainstem at 4-5 months. Phosphorylated tau-positive neuritic processes have been observed in the vicinity of all congophilic amyloid deposits, but no fibrillar tau inclusions are seen.  Cognitive deficits in spatial learning and memory in the Morris water maze reported at 7 months. Impaired reversal learning of a food-rewarded four-arm spatial maze task at 8 months. Aβ42 concentration in CSF decreases with age, with a 50% reduction by 6 months and an 80% reduction by 18 months. Aβ40 concentration also decreases, but less robustly (45% by 18 months). CSF concentration of total tau increases, starting at 6 months, and reaches a 5-fold increase by 18 months. Available through Mathias Jucker Radde et al., 2006 Yes
<p>-</p>, <p>APPswe/PSEN1dE9/MAPT</p>, <p>APPswe/PSEN1dE9/CaMKIIa-tTa/TRE-Tg21221</p> B6.C3 x B6.129 x FVB APP, PSEN1, MAPT APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 APPswe/PSEN1dE9 mice were crossed with B6.129-Tg(CK-tTa) mice where the CaMKIIa promotor drives expression of tetracycline transactivator (tTA) in forebrain neurons. Offsping were then crossed to the Tg21221 line with a responder transgene of wildtype human tau. APP: Transgenic; PSEN1: Transgenic; MAPT: Transgenic Alzheimer's Disease Tau accumulations, dystrophic neurites, astrocytosis, neuronal loss, and synapse loss were more pronounced adjacent to cortical plaques. Tangles were not observed. No data. N/A APPswe/PSEN1dE9 mice available through JAX MMRRC Stock# 034829. Jackson et al., 2016 Yes
<p>-</p>, <p>App<sup>SAA</sup></p>, <p>App<sup>SAA</sup> Knock-in</p>, <p>App<sup>SAA</sup> KI</p>, <p>APP-SAA KI</p>, <p>hAbetaSAA</p>, <p>hAbeta<sup>Swe,Arc,Aus</sup></p> B6(Cg)-Apptm1.1Dnli/J C57BL/6J App APP K670_M671delinsNL (Swedish), APP E693G (Arctic), APP T714I (Austrian) Homologous recombination was used to humanize the Aβ sequence and introduce the FAD-linked Swedish, Arctic, and Austrian mutations into the murine App gene. App: Knock-In Alzheimer's Disease Homozygotes: Amyloid plaques and plaque-associated microgliosis from 4 months of age; cerebral amyloid angiopathy and dystrophic neurites from 8 months of age. Heterozygotes: Amyloid plaques at 16 months of age. Unknown. Increased levels of CSF total tau and neurofilament light chain in AppSAA homozygous mice at 8 months of age. Significant alterations of the transcriptomes and lipidomes in microglia of AppSAA homozygotes. Available from The Jackson Laboratory Stock# 034711. Xia et al., 2021 Yes
<p>-</p>, <p>Tg2576;Pdgfrβ<sup>+/-</sup></p> APPsw mice on C57BL/6; Pdgfrβ+/- mice on 129S1/SvlmJ. APP, PDGFRB APP K670_M671delinsNL (Swedish) Progeny of APPsw transgenics (Tg2576) crossed with pericyte-deficient mice. Tg2576 express human APP with the Swedish double mutation driven by the hamster prion promoter. Pericyte-deficient mice were made by disrupting the Pdgfrβ gene using a PGKneobpA expression cassette to replace a 1.8 kb genomic segment spanning the signal peptide to the second immunoglobulin domain of PDGFRβ. APP: Transgenic; PDGFRB: Knock-Out Alzheimer's Disease Amyloid plaques; elevated brain interstitial human and murine Aβ due to reduced clearance of soluble Aβ, cerebral amyloid angiopathy, tau hyperphosphorylation and related pathology. Neurite loss and neuronal loss in the cortex and hippocampus. Age-associated cognitive impairment as measured by hippocampal-dependent tasks, including nest building, burrowing, and novel object recognition. Progressive loss of pericytes due to reduced Pdgfrβ signaling. Early and progressive blood brain barrier breakdown, indicated by cerebral accumulation of IgG. Reduced microvascular circulation, indicated by reduced capillary length. Available through Berislav Zlokovic Sagare et al., 2013 Yes
<p>-</p>, <p>APPSwDI/NOS2 bigenic mice</p>, <p>APPSDI/NOS2KO</p>, <p>CVN</p> B6.Cg-Nos2tm1Lau Tg(Thy1-APPSwDutIowa)BWevn/Mmjax C57BL/6J; C57BL/6N APP, NOS2 APP K670_M671delinsNL (Swedish), APP E693Q (Dutch), APP D694N (Iowa) APPSwDI x NOS2 knockout animals. APPSwDI transgene expresses APP (isoform 770) with Swedish, Dutch, and Iowa mutations under the control of the mouse Thy1 promoter. NOS2 was disrupted by homologous recombination. The calmodulin binding domain of NOS2 was replaced by the neomycin resistance gene and the reading frame disrupted. APP: Transgenic; NOS2: Knock-Out Alzheimer's Disease Plaques especially in the thalamus and subiculum. Aggregated, hyperphosphorylated tau tangles. Neuronal loss especially of NPY neurons in the hippocampus and subiculum. More severe pathology than Tg-SwDI alone. Severe learning and memory deficits. Impaired spatial memory compared to Tg-SwDI as measured by the radial arm maze and the Barnes maze at 52-56 weeks. Decreased neuropeptide Y staining throughout the hippocampus, particularly in the CA3 region and subiculum. The Jackson Lab; available through the JAX MMRRC Stock# 034849; Cryopreserved. Charles River: CVN mouse Colton et al., 2008, Wilcock et al., 2008 Yes
<p>-</p>, <p>APPSw</p>, <p>hAPPSwe (line 71)</p>, <p>hAPPSwe (line 72)</p>, <p>huAPPSw</p> B6.D2-Tg(Thy1-APPSwe)71Blt; B6.D2-Tg(Thy1-APPSwe)72Blt C57BL/6, DBA/2, crossed to C57BL/6 APP APP K670_M671delinsNL (Swedish) Transgene with human APP751 with the Swedish mutation driven by the Thy1.2 promoter. APP: Transgenic Alzheimer's Disease Amyloid plaques by 17-18 months in the neocortex and hippocampus with detection of 5-10 fold more Aβ40 than Aβ42. Plaque burden significantly lower than in the double transgenic PS2APP. Lower levels of insoluble Aβ40 and Aβ42 than the PS2APP mouse at 16-18 months. Unknown. Available through Laurence Ozmen Richards et al., 2003 No
<p>R1.40</p>, <p>APP<sup>K670/M671</sup></p>, <p>R1.40-YAC</p> B6.129-Tg(APPSw)40Btla/Mmjax (129X1/SvJ x 129S1/Sv)F1-Kitl&lt;+&gt; APP APP K670_M671delinsNL (Swedish) A 650 kb YAC transgene containing the entire human APP gene and ~250 kb of flanking sequence was mutated to include the Swedish mutation (K670N/M671L). Founder animals (line R1.40) were backcrossed to C57BL/6J. APP: Transgenic Alzheimer's Disease By 14-16 months, homozygotes have diffuse and compact Aβ deposits in the frontal cortex, by 18-20 months plaques throughout the cortex and olfactory bulb with occasional deposits in the corpus callosum and hippocampus. No tangles, but some changes in phosphorylated tau. Reactive astrocytes and microglia by 14-16 months. Unknown. Increased mortality in young homozygous animals, especially females. At 3-4 months mice maintained on the C57BL/6J background exhibit spontaneous seizure-like activity as measured by EEG and are more susceptible to kainic acid-induced seizures. The Jackson Lab; available through the JAX MMRRC Stock# 034831; Cryopreserved Lamb et al., 1997 Yes
<p>-</p>, <p>APP(695)Swe</p> C3B6-Tg(APP695)3Dbo/Mmjax C3H/HeJ x C57BL/6J; backcrossed to C57BL/6J APP APP K670_M671delinsNL (Swedish) Transgene is a chimeric mouse/human APP (isoform 695) with a "humanized" Aβ domain and the Swedish mutation under the control of the mouse prion protein promoter. APP: Transgenic Alzheimer's Disease Age-associated increase in Aβ40 and Aβ42 and some amyloid deposition at advanced age. Congenic animals showed normal reference and working memory up to 12-14 months. The Jackson Lab; available through the JAX MMRRC Stock# 034828; Cryopreserved Borchelt et al., 1996, Savonenko et al., 2003 Yes
B6.Cg-Tg(Prnp-App/APPswe)E1-2Dbo/Mmjax C3H/HeJ x C57BL/6J; backcrossed to C57BL/6J APP APP K670_M671delinsNL (Swedish) Transgene is a chimeric mouse/human APP (isoform 695) with a "humanized" Aβ domain carrying the Swedish mutation under the control of the mouse prion protein promoter. APP: Transgenic Alzheimer's Disease Age-dependent increase in Aβ42, with low levels at 6-14 months and high levels at 24-26 months. No cognitive impairment in tasks of reference or working memory at 12-14 months. More than half of the female hemizygous mice do not survive past 15 months of age. The Jackson Lab; available through the JAX MMRRC Stock# 034835; Cryopreserved Savonenko et al., 2003, Borchelt et al., 1996 No
<p>-</p>, <p>APP YAC Swe/Lon (line J1.96)</p>, <p>B6-J1-96</p> B6.129S4-Tg(APPSwLon)96Btla/Mmjax 129S4/SvJae-derived J1 ES cells; backcrossed to C57BL/6 APP APP K670_M671delinsNL (Swedish), APP V717I (London) A 650 kb YAC transgene containing the entire human APP gene carrying the Swedish and London mutations with ~ 250 kb of flanking sequence; founder animals (line J1.96) have a single copy of the transgene. APP: Transgenic Alzheimer's Disease No amyloid plaques observed at 2 years. Unknown. The Jackson Lab; available through the JAX MMRRC Stock# 034837; Cryopreserved Lamb et al., 1997 No
<p>-</p>, <p>APPSwe (line C3-3)/PSEN1(A246E)(line N-5)</p>, <p>APP/PS1</p>, <p>APPswe + PS1 (A246E)</p>, <p>APP + PS1</p>, <p>AP mouse</p>, <p>C3-3/N-5</p> B6C3-Tg(APP695)3Dbo Tg(PSEN1)5Dbo/Mmjax Origin: (C57BL/6J x C3H/HeJ)F2 APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1 A246E Double transgenic mice; cross of mice expressing human PSEN1 with the A246E mutation driven by the mouse prion protein promoter with mice expressing chimeric APP (isoform 695) with the Swedish mutation driven by the mouse prion promoter. Chimeric APP was created by replacing the mouse Aβ sequence with the cognate human sequence. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques by 9 months, starting in the hippocampus and subiculum. Plaques later develop in the cortex; the striatum and thalamus are relatively spared. Amyloid pathology is more severe in females. Dystrophic neurites and gliosis in the cortex and hippocampus. Poor nest building. Reduced retention in a learned passive avoidance task. Increased immobility time in forced swim task. Age-associated impairment in acquisition and retention in the Morris water maze. No impairment in a position discrimination T-maze task. Increased irritability. The Jackson Lab: Stock# 003378; Cryopreserved Borchelt et al., 1997, Borchelt et al., 1996 Yes
<p>-</p>, <p>APPSwe(line C3-3) X PS1dE9 (line S-9)</p>, <p>C3-3/PS1-dE9</p>, <p>C3-3 x S-9</p> B6.Cg-Tg(APP695)3Dbo Tg(PSEN1dE9)S9Dbo/J Line C3-3: C57BL/6J; Line S-9: hybrid strain C3H/HeJ;C57BL/6J) backcrossed to C57BL/6J APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 Double transgenic mice: 1) Line C3-3: mice express a chimeric mouse/human APP gene (isoform 695) carrying the Swedish mutation and 2) Line S-9: mice express a mutant human PSEN1 gene carrying the deletion of exon 9 (dE9) driven by the mouse prion promoter. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Elevated Aβ42 and plaques in the hippocampus and cortex. No tangles. Reduced cholinergic markers. Age-related cognitive deficits; episodic memory more sensitive than reference memory. No differences at 6 months, but detectable at 18 months. At 19 months, small but significant decrease in acetylcholinesterase activity in the hippocampus and choline acetyl transferase (ChAT) in the hippocampus and cortex. The Jackson Lab; available through the JAX MMRRC Stock# 034833; Cryopreserved Savonenko et al., 2005 Yes
<p>-</p>, <p>APP/PS1</p>, <p>C57BL/6J APPswePsen1de9</p>, <p>B6.APB<sup>Tg</sup></p> B6.Cg-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax C57BL/6J APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 Mice carry two transgenes, a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9, each controlled by the mouse prion protein promoter. Transgenic mice on the original hybrid C57BL/6 x C3H background were backcrossed with C57BL/6J mice. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques begin to emerge in the cortex at about 4 months of age and in the hippocampus at about 6 months. Gliosis and dystrophic neurites are associated with plaques. Amyloid angiopathy has been observed in the retina. Hyperactivity is apparent by 6 months. Deficits in the Morris water maze emerge between 6 and 10 months and worsen with age. A substantial proportion of APPswe/PSEN1dE9 mice exhibit electrographic and behavioral seizures. Available from the Jackson Laboratory, JAX MMRRC Stock# 034832 (formerly Jackson Lab Stock #005864) Minkeviciene et al., 2008, Minkeviciene et al., 2009 Yes
<p>-</p>, <p>APP/PS1</p>, <p>APPswe/PS1deltaE9</p>, <p>line 85</p>, <p>APP(swe) + PSEN1DeltaE9</p>, <p>APPdE9</p>, <p>Borchelt mice</p> B6C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax C57BL/6;C3H APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 Co-injection of a vector for chimeric mouse/human APP carrying the Swedish mutation and a second for mutant PSEN1 (deltaE9) controlled by independent mouse prion protein promoter elements. The two transgenes co-integrated and co-segragate as a single locus. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Occasional Aβ deposits by 6 months with abundant plaques in the hippocampus and cortex by 9 months and a progressive increase in plaques up to 12 months. No tangles. Decrease in synaptic markers and increase in complement immunoreactivity. Cognitive impairment (e.g., deficits in spatial memory and contextual memory). Changes in spontaneous behavior (e.g., nest-building, burrowing). Kinked tail phenotype that is believed to be due to genetic background. The Jackson Lab; available through the JAX MMRRC Stock# 034829 (formerly Jackson Lab Stock # 004462); Live Jankowsky et al., 2001, Jankowsky et al., 2004 Yes
<p>-</p>, <p>NSE-APPsw</p> Origin: C57BL/6 x DBA/2 APP APP K670_M671delinsNL (Swedish) Transgene containing human APP (isoform 695) bearing the Swedish mutation under the control of neuron specific enolase (NSE) promoter. APP: Transgenic Alzheimer's Disease Increased Aβ42 in the cortex and hippocampus of 12 month old mice, but no plaques. Increased tau phosphorylation and TUNEL-stained nuclei relative to control mice. In water maze tests, 12 month old mice had longer escape latencies than age-matched control mice. Metallothionein expression was increased in brain astrocytes and was thought to attenuate Aβ-induced neurotoxicity.  Increased Cox-2 and caspase-3 compared to age-matched control mice.   Available through Yong K Kim Hwang et al., 2004 No
Knock-in of APP(V642I) Origin:C57BL/6 x CBA; chimeric mice breed to CD-1 mice APP APP V717I (London) Targeted knock-in of the V642I mutation into exon 17 of the mouse APP gene using homologous recombination and the Cre-loxP system. APP: Transgenic Alzheimer's Disease Increased Aβ42(43) relative to Aβ40 at 29 months, but without neuritic plaques, neurofibrillary tangles, massive neuronal loss, or brain atrophy. At 27-29 months mice displayed long-term memory deterioration. Acquisition of spatial memory is slightly affected, but no deterioration in short-term working memory. No difference in open field test or elevated plus maze suggesting no difference in overall behavioral patterns or activity levels. Unknown Kawasumi et al., 2004 Yes
<p>-</p>, <p>APPlon</p>, <p>APP-london</p>, <p>APPLd</p>, <p>APP-ld</p>, <p>APP(V717I)</p>, <p>APP[V717I]</p>, <p>APP.V717I</p>, <p>APP(London) (line 2)</p>, <p>APP/LD/2</p> Tg(Thy1-APPLon)2Vln/0 Originally generated on FVB/N background; available at reMYND as C57BL/6xFVB/N APP APP V717I (London) Transgene containing human APP (isoform 695) with the London mutation driven by the Thy1 promoter. APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy Plaques start in the subiculum, spreading to the frontal cortex as dense and diffuse aggregates. Prominent amyloid deposits in brain vessels after 15 months. Microbleeds. Amyloid-associated inflammation. CSF Aβ42/Aβ40 ratio decreases from 15 months. Dystrophic neurites containing hyperphosphorylated tau, but no tangle pathology. From the age of 6 months, spatial and non-spatial orientation and memory deficits by Morris water maze. Impaired associative learning. Increased agitation/anxiety from 8 weeks. Reduced ambulation, especially with age. Hyperactivity and aggression. Increased mortality (72% by day 180). Increased incidence of seizures. Available through the KU Leuven Research and Development Office; the CRO reMYND offers research services with this line. Moechars et al., 1999 Yes
<p>-</p>, <p>APPxPS1</p>, <p>APP(V717I)x PS1(A246E)</p>, <p>APP[V717I]x PS1[A246E]</p>, <p>APP.V717I x PS1.A246E</p> Tg(Thy1-APPLon)2Vln/0; Tg(Thy1-PSEN1*A246E)2Vln/0 Originally generated on FVB/N background; available at reMYND as C57BL/6xFVB/N APP, PSEN1 APP V717I (London), PSEN1 A246E The transgene overexpresses the mutant human amyloid protein precursor APP (isoform 695), which bears the London (V717I) mutation, and human presenilin-1 with the A246E mutation, both under the control of the neuron-specific murine Thy1 promoter. APP: Multi-transgene; PSEN1: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy Soluble, oligomeric Aβ at 2 months and increases with age. Amyloid plaques at 6-9 months, earlier than APP(V717I) single transgenics. Plaques start in the subiculum and spread to the frontal cortex. Amyloid-associated inflammation. CAA pathology at 8 months; microbleeds at 12-15 months. Dystropic neurites containing hyperphosphorylated tau, but no tangle pathology. From the age of 5 months, spatial and non-spatial orientation and memory deficits by Morris Water Maze. Impaired associative learning, hyperactivity, anxiety, and aggression. The CRO reMYND offers research services with this line. Dewachter et al., 2000 Yes
APPSw/Ind/Arc, APPSwedish/Indiana/Arctic, hAPP Arc line Inbred C57BL/6 APP APP K670_M671delinsNL (Swedish), APP V717F (Indiana), APP E693G (Arctic) A human APP minigene with the Swedish, Indiana, and Arctic mutations driven by the platelet-derived growth factor β-chain promoter. APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy Parenchymal neuritic plaques by 2 months accompanied by dystrophic neurites. Prominent hippocampal Aβ deposition by 3-4 months. Relatively low Aβ42/Aβ40 ratio. Comparable cerebrovascular amyloid deposition to J20. At 3-4 months the Arc48 mouse was able to learn a task involving escape to a cued platform in the Morris water maze, but had an impaired ability to use extramaze cues to navigate to the hidden platform. Premature lethality. Trend toward hyperactivity. Reduced calbindin and Fos levels in the dentate gyrus. Cryopreserved. Contact Lennart Mucke Cheng et al., 2004 Yes
arcAbeta Origin: B6D2 F1 APP APP K670_M671delinsNL (Swedish), APP E693G (Arctic) Human APP695 transgene containing the Swedish (K670N/M671L) and Arctic mutation (E693G) was generated by site-directed mutagenesis. APP: Transgenic Alzheimer's Disease At 6 months intracellular punctate deposits of Aβ abundant in cortex and hippocampus, but overt β-amyloid plaques not apparent until 9-15 months. Severe CAA also present at this age with dense Aβ aggregates in blood vessels walls and spreading into the parenchyma. Cognitive impairments from the age of 6 months measured in the Morris water maze and Y-maze. Deficits in synaptic plasticity, LTP, and functional connectivity as measured by resting-state fMRI. Unknown Knobloch et al., 2007 Yes
B6;CB-Tg(Thy1-PSEN1*M146V/Thy1-APP*swe)10Arte Co-injection of transgenes into B6CBF1 oocytes, back-crossed to C57BL/6 APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1 M146V Co-integration of two transgenes, mutant APP carrying the K670N/M671L mutation, and mutant PSEN1 carrying the M146V mutation, both under the control of the Thy-1 promoter. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Robust early plaque development (by 3 months in homozygotes, 5 months in hemizygotes), predominantly congophilic dense-core amyloid plaques surrounded by dystrophic neurites and gliosis. Some diffuse plaques and cerebral amyloidosis. No tau tangles. Neurons have reduced dendritic length, surface area, and branches. Age-related learning and memory deficits, especially episodic memory, in select paradigm-specific tasks by 12 months. Good breeding capabilities and no premature death. Taconic: Stock #16347 Willuweit et al., 2009 Yes
<p>-</p>, <p>Atg16L<sup>ΔWD</sup></p>, <p>Atg16l1<sup>E230</sup></p>, <p>Atg16L1-WD-deficient</p>, <p>Atg16L1-WD knockout</p> Mixed 129, C57BL/6 Atg16l1 Two premature stop codons were introduced after the codon for E230, in exon 6 of the Atg16L gene. Mice express a prematurely truncated version of the autophagy protein ATG16L1, missing the WD (tryptophan-aspartate) repeat domain. Atg16l1: Knock-Out Alzheimer's Disease Intracellular and extracellular Aβ deposits, but no dense-core plaques. Microgliosis and neuron loss in 2-year-old mice. Deficits in the sucrose-preference test, spontaneous alternation in the Y-maze, and novel object recognition test. Impaired long-term potentiation at CA3-CA1 synapses. Mice are available from Ulrike Mayer or Thomas Wileman. Heckmann et al., 2020 Yes
<p>-</p>, <p>Atp13a2 null</p>, <p>Atp13a2 KO</p> Atp13a2tm1.1Wtd/J Mixed C57BL6/129 Atp13a2 In this floxed mouse model, one loxP site is present upstream exon 2 and the second loxP site is present downstream exon 3 of the Atp13a2 gene. It was generated using homologous recombination of a targeting vector electroporated into B6/129 embryonic stem cells, with the aid of an FRT-flanked neomycin resistance cassette that was subsequently removed. Atp13a2: Knock-Out Parkinson's Disease Adult-onset Atp13a2 KO in the ventral midbrain (via AAV-Cre delivery) resulted in neuropathology, including dopaminergic neuronal degeneration in the SN, which was not observed in germline Atp13a2 KO mice. Motor function partially impaired in germline Atp13a2 KO mice, including defects on the open-field and tail suspension tests, but not on the balance beam or Rotarod. Impairments in autophagy and lysosomal processing in neural tissues were detected in mice with germline, or adult-onset, ventral midbrain Atp13a2 KO. Available through The Jackson Laboratory, Stock# 028387, Cryopreserved. Kett et al., 2015 Yes
<p>-</p>, <p>BACE1<sup>fl/fl/UbcCreER</sup> X 5xFAD</p> C57BL/6J Bace1, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V 5xFAD mice were crossed with Bace1fl/fl mice (Hu et al., 2018) to generate 5xFAD mice homozygous for a floxed Bace1 gene (“Bace1fl/fl/5xFAD). Bace1fl/fl/5xFAD mice were then bred to BACE1 conditional knock-out (Hu, Yan) mice. Bace1: Conditional Knock-out; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques, reactive astrocytes and microglia, and dystrophic neurites accumulate up to day 120, but to a lesser degree than in control 5xFAD (5xFAD mice homozygous for a floxed Bace1 gene), then recede thereafter. Normal contextual and cued fear conditioning, tested at 8 to 10 months of age. Deficit in long-term potentiation at Schaffer collateral–CA1 synapses in slices from 10- to 12-month-old mice, but less severe than that seen in slices from control mice (5xFAD mice homozygous for a floxed Bace1 gene). Bace1fl/fl not yet available. UBC-Cre-ERT2 available from The Jackson Laboratory, Stock# 007001. 5xFAD available from The Jackson Laboratory, JAX MMRRC Stock# 034848. Hu et al., 2018 Yes
<p>-</p>, <p>Bace1 cKO</p>, <p>BACE1<sup>fl/fl</sup>;R26CreER<sup>T2</sup>-TAM</p> C57BL6 Bace1 Mice in which exon 2 of Bace 1 is flanked by LoxP sites (Ou-Yang et al., 2018) were crossed with R26CreERT2mice (Ventura et al., 2007), which carry a transgene encoding Cre recombinase fused to the estrogen receptor, inserted at the ROSA26 locus. Bace1: Conditional Knock-out Alzheimer's Disease Defects in axonal organization. Normal learning and memory in the Morris water maze, normal alternation in the Y-maze test of working memory, and normal cued and contextual fear conditioning; possible hyperactivity in novel situations. BACE1fl/fl available through Robert Vassar; R26CreERT2 available through The Jackson Laboratory Stock# 008463, Live Ou-Yang et al., 2018 Yes
<p>-</p>, <p>BACE1 cKO</p>, <p>BACE1<sup>fl/fl/UbcCreER</sup></p> C57BL/6J Bace1 These mice were generated by crossing Bace1fl/fl mice (Hu et al., 2018), in which exon 2 of the mouse Bace1 gene is flanked by loxP sites, with UBC-Cre-ERT2 mice (The Jackson Laboratory, Stock# 007001), which carry a transgene encoding Cre recombinase fused to a modified human estrogen receptor, driven by the ubiquitin C promoter. Bace1: Conditional Knock-out Alzheimer's Disease No gross morphological changes observed. BACE1-deficient mice and Bace1fl/fl mice performed similarly in tests of contextual and cued fear conditioning at 8 to 10 months of age. Impaired long-term potentiation at Schaffer collateral–CA1 synapses in slices obtained from 10- to 12-month-old mice. Bace1fl/fl not yet available. UBC-Cre-ERT2 available from The Jackson Laboratory, Stock# 007001. Hu et al., 2018 Yes
<p>-</p>, <p>Bace1 cKO</p>, <p>BACE1<sup>fl/fl</sup>;CamKIIα-iCre</p> C57BL6 Bace1 Mice in which exon 2 of Bace1 is flanked by LoxP sites (BACE1fl/fl) were crossed with mice carrying a transgene encoding Cre recombinase driven by the CamKIIα promoter (Casanova et al., 2001). Bace1: Conditional Knock-out Alzheimer's Disease Hypomyelination and defects in axon organization. Delayed learning, but normal memory, in the Morris water maze; normal alternation in the Y-maze test of working memory, normal cued and contextual fear conditioning. Hyperactivity in when placed in novel environments. Spontaneous behavioral seizures and epileptiform discharges in EEGs. BACE1fl/fl available through Robert Vassar;  CamKIIα-iCre available through the European Mouse Mutant Archive (EMMA) ID# EM: 01153, cryopreserved, sperm Ou-Yang et al., 2018 Yes
<p>-</p>, <p>Bace1 cKO</p>, <p>BACE1<sup>flox/flox</sup>;RosaCreERT2<sup>+/WT</sup></p> C57BL/6-Bace1tm1.1mrl C57BL/6N Bace1 Mice in which exon 2 of Bace1 is flanked by LoxP sites were crossed with R26-CreERT2 mice, which carry a transgene encoding Cre recombinase fused to the estrogen receptor, inserted at the ROSA26 locus. Bace1: Conditional Knock-out Alzheimer's Disease None observed: hippocampal mossy fiber organization and sciatic-nerve myelination were normal. Performed similarly to controls in a battery of tests (Y-maze, contextual fear conditioning, pre-pulse inhibition, open field, and light-dark transition task). Deficit in long-term potentiation at Schaffer collateral–CA1 synapses. BACE1flox/flox available through Taconic Model# 8263, Cryopreserved. RosaCreERT2 (R26-CreERT2) available through The Jackson Laboratory Stock# 008463, Live.  Lombardo et al., 2019 Yes
<p>-</p>, <p>BACE1<sup>-/-</sup></p>, <p>BACE1 KO</p> B6.129-Bace1tm1Pcw/J C57BL/6J BACE1 Homologous recombination was used to disrupt a 2kb section of BACE1 containing exon 1 replacing it with a neomycin selection cassette and the HSV thymidine kinse gene. BACE1: Knock-Out Alzheimer's Disease Hypomyelination in the hippocampus and cerebral cortex, but normal axonal development. Increased thermal pain sensitivity as measured by a hot plate test. Decreased grip strength. Homozygous mice are viable, fertile, normal in size. No BACE1 protein is detected by Western blot. Primary cultures of cortical neurons do not secrete Aβ1-40/42, Aβ11-40/42 or β-C terminal fragments (β-CTFs). The Jackson Lab: Stock# 004714; Live Cai et al., 2001 No
<p>-</p>, <p>BACE2delta6</p>, <p>BACE2 KO</p> B6;129P2-Bace2tm1Bdes/J Strain of origin: 129P2/OlaHsd BACE2 Cre mediated recombination was used to remove exon 6 of BACE2. A targeting vector containing a loxP site and hygromycin resistance gene flanked by FRT sites was introduced into intron 5 and a second loxP site was inserted within intron 6. Heterozygous mice were crossed with mice expressing Cre under the ubiquitous phosphoglycerate kinase promoter to delete exon 6 in progeny. BACE2: Knock-Out Alzheimer's Disease Not observed. Not observed. BACE2 deficient fibroblasts produced higher levels of Aβ compared with wild-type cells. The Jackson Lab: Stock# 005618; Cryopreserved Dominguez et al., 2005 No
BRI2-Aβ40 B6.Cg-Tg(Prnp-ITM2B/APP695*40)1Emcg/J B6C3, backcrossed to C57BL/6J to generate congenic strain Construct encodes a fusion protein of the BRI protein and Aβ40 driven by the mouse prion promoter; Aβ40 is secreted through proteolytic cleavage of the protein at a furin cleavage site immediately preceding Aβ40. Transgenic Alzheimer's Disease No overt amyloid pathology or detergent-insoluble amyloid-β. Hemizygous mice on a mixed background (C57/B6//C3H) have intact cognition as measured by fear conditioning at 12 and 14-17 months. The Jackson Lab: Stock# 007180; Cryopreserved McGowan et al., 2005 No
BRI2-Aβ42, BRI-Abeta42 B6.Cg-Tg(Prnp-ITM2B/APP695*42)A12Emcg/J B6C3, backcrossed to C57BL/6J to generate congenic strain Construct encodes a fusion protein of the BRI protein and Aβ42 driven by the mouse prion promoter. Aβ42 is secreted through proteolytic cleavage of the protein at a furin cleavage site immediately preceding Aβ42. Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy Detergent-insoluble amyloid-β appearing with age and cored plaques as early as 3 months in the cerebellum. Variable forebrain pathology later with extracellular Aβ plaques in the hippocampus and entorhinal/piriform cortices at 12 months. Age-associated congophillic amyloid angiopathy. No tangles or neuronal loss. On a mixed (C57/B6//C3H) background hemizygous mice have intact cognition as measured by fear conditioning at 12 months and 14-17 months despite accumulating amyloid. The Jackson Lab: Stock# 007182; Cryopreserved McGowan et al., 2005 Yes
<p>Brown</p>, <p>C9-BAC[GGGGCC]500</p> SJL/B6 C9orf72 Hexanucleotide repeat in C9ORF72 This transgenic mouse carries a bacterial artificial chromosome (BAC) containing exons 1 through 6 of human C9orf72 with ~500 GGGGCC repeat motifs and ~140.5 kb upstream. C9orf72: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Widespread RNA foci throughout the nervous system starting at 3 months of age, especially comprised of sense transcript. Dipeptide repeats (e.g., poly-GP) as soluble protein and insoluble aggregates. No neurodegeneration. No TDP-43 aggregation, gliosis, inflammation, or synapse loss. No overt behavioral abnormalities compared to non-Tg controls. Assessment included grip strength, Rotarod performance, and intruder test. Viable, fertile, born in Mendelian ratios. Available through Robert Brown Peters et al., 2015 Yes
Baloh/Lutz, C9-BAC[GGGGCC]100-1000, Tg(C9orf72_3) line 112, Line F112 C57BL/6J-Tg(C9orf72_i3)112Lutzy/J C57BL/6J C9orf72 Hexanucleotide repeat in C9ORF72 This transgenic mouse carries a bacterial artificial chromosome (BAC) containing full-length human C9ORF72 sequence with ~100-1000 repeats. C9orf72: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Widespread RNA foci throughout the nervous system first assessed at 3 months of age. Soluble dipeptide repeats (e.g., poly-GP) and insoluble aggregates. No neurodegeneration. No TDP-43 aggregation, gliosis, inflammation, or obvious synapse loss. No behavioral abnormalities compared to non-Tg controls at either young age (3 months) or advanced age (18 months). Tests included: grip strength, Rotarod performance, open-field, three-chamber, and Y-maze. Viable, fertile, born in Mendelian ratios. The Jackson Lab: Stock# 023099; Live O'Rourke et al., 2015 Yes
<p>-</p>, <p>(G<sub>4</sub>C<sub>2</sub>)<sub>149</sub></p>, <p>149-repeat mice</p> C57BL/6J C9orf72 Hexanucleotide repeat in C9ORF72 An adeno-associated viral (AAV) vector was used to deliver 149 repeats of the hexanucleotide GGGGCC motif, along with the 5' (119 bp) and 3' (100 bp) flanking regions of the C9ORF72 gene, driven by the β-actin promoter. Virus was injected into the lateral ventricles of wild-type pups on postnatal day 0. C9orf72: Virus Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Intranuclear foci containing antisense and antisense repeat RNA; cytoplasmic inclusions containing sense and antisense dipeptide repeat proteins; accumulation of phosphorylated TDP-43 and stress granule-associated proteins; neuron loss and gliosis. Motor and cognitive deficits emerge between 3 and 6 months of age. Hyperactivity seen by 3 months. Mislocalization of RanGAP1 suggests nucleocytoplasmic transport defects. Unknown. Chew et al., 2019 Yes
<p>-</p>, <p>66-repeat mice</p>, <p>Petrucelli’s AAV C9 model</p> C57BL/6 C9orf72 Hexanucleotide repeat in C9ORF72 An adeno-associated viral (AAV) vector was used to deliver a sequence of 66 repeats of the hexanucleotide, GGGGCC. The virus was injected into the cerebral ventricles of P0 pups. C9orf72: Virus Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Nuclear RNA foci in neurons, dipeptide aggregates (GA, GP, and GR), cytoplasmic inclusions of phosphorylated TDP-43, neuronal loss, brain atrophy, and gliosis. Subtle behavioral deficits including anxiety-like behavior, hyperactivity, and antisocial behavior. Subtle motor impairment and failure to improve on the Rotarod. Reduced body weight in females by 6 months. Viral construct available through Leonard Petrucelli Chew et al., 2015 Yes
<p>-</p>, <p>C9orf72 KO</p>, <p>3110043O21Rik Knock-out</p> 3110043O21Riktm1(KOMP)Mbp C57BL/6N C9orf72 The mouse 3110043O21Rik gene (homologue of human C9orf72) was inactivated by deleting a region containing exons 2-6, which includes the start codon. The targeting vector contained expression cassettes, flanked by FRT sites, for lacZ and neo as selectable markers. C9orf72: Knock-Out Frontotemporal Dementia, Amyotrophic Lateral Sclerosis Chromatolytic structures are observed with H&E staining, in gray and white matter of the spinal cord. Neurodegeneration not present. Normal sensorimotor coordination and limb strength. Reduced activity in open-field test. Spleens and lymph nodes enlarged by 1 month, size increases with age. Histology shows enlarged debris-filled cells. Available through the UC Davis Knockout Mouse Project (KOMP) Repository, gene 3110043021Rik; Cryopreserved O'Rourke et al., 2016 Yes
<p>-</p>, <p>CamKII-tTA;(GR)<sub>80</sub> (line 16)</p>, <p>CamKII;(GR)<sub>80</sub></p> C57BL/6 CamKII-tTA;(GR)80 mice are produced by crossing a responder line carrying a (GGXCGX)80 sequence downstream of a tetracycline operon–responsive element (TRE) to an activator line expressing a tetracycline-controlled transactivator (tTA) under control of the CaMKIIα promoter. Bi-transgenic progeny constitutively express poly(GR) until transgene expression is suppressed by administration of the tetracycline analog doxycycline (DOX). Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Neuron loss in the frontal cortex, beginning between 3 and 6 months of age. Microgliosis and astrogliosis evident at 6 and 9 months, respectively. No TDP-43 inclusions seen in mice studied up to 8 months of age. DNA damage and mitochondrial abnormalities observed. Deficits in social behavior and increased anxiety emerge between 3 and 6 months. Working memory is intact at least through 9 months of age. Morphological defects in mitochondria seen in mice as young as 3 months of age. Disease-related phenotypes were prevented or reversed by reducing levels of poly(GR) in adult mice. Unknown. Choi et al., 2019 Yes
CAST.Cg-Tg(APPswe,PSEN1dE9)85Dbo/How CAST/EiJ APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 Mice carry two transgenes, a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9, each controlled by the mouse prion protein promoter. Transgenic mice on a congenic C57BL/6J background were backcrossed with CAST/EiJ mice for at least six generations. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques, plaque-associated gliosis, cerebral amyloid angiopathy; possible neuron loss in hippocampal area CA1. Transgenic mice are hyperactive. Working memory (spontaneous alternation in the Y-maze) is normal at 7 to 8 months, but short-term memory (tested in the Y-maze) is impaired in males (data from females is not available, as wild-type females are unable to perform this test). Available from The Jackson Laboratory, Stock #25973. Onos et al., 2019 Yes
<p>-</p>, <p>APOE4/Trem2*R47H/Ceacam1 knock-out</p> B6.Cg-Apoetm1.1(APOE*4)Adiuj Ceacam1em#1Adiuj Trem2em1Adiuj/J C57BL/6J APOE, Ceacam1, Trem2 TREM2 R47H CRISPR/cas9 was used to generate a knock-out mutation of the Ceacam1 gene of double mutant mice with a humanized APOE4 gene and the p.R47H point mutation knocked into the mouse Trem2 gene (B6(SJL)-Apoetm1.1(APOE*4)Adiuj Trem2em1Adiuj/J, The Jackson Labortory Stock# 028709). APOE: Knock-In; Ceacam1: Knock-Out; Trem2: Knock-In Alzheimer's Disease Unknown. Unknown. The Jackson Laboratory, Stock# 030673. Cryopreserved. The Jackson Laboratory Yes
B6(SJL)-Apoetm1.1(APOE*4)Adiuj Clasp2em1Adiuj Trem2em1Adiuj/J C57BL/6J Clasp2, APOE, Trem2 TREM2 R47H CRISPR/cas9 was used to generate a knock-in L163P mutation of the Clasp2 gene of APOE4/Trem2*R47H mice—double-mutant mice with a humanized Apoe (ε4 allele) gene and the R47H point mutation knocked into the mouse Trem2 gene. Clasp2: Knock-In; APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease Unknown. Unknown. The Jackson Laboratory, Stock# 031944. Cryopreserved. The Jackson Laboratory Yes
fPS1/fPS1Δ;Nestin-Cre (PS1 cKO) C57BL6/129 PSEN1 PS1 inactivation in neuronal progenitor cells (NPCs) and NPC-derived neurons and glia was achieved by crossing a floxed PS1 mouse with a Nestin-Cre transgenic mice. PSEN1: Conditional Knock-out Alzheimer's Disease Premature differentiation of neural progenitor cells results in reduced cells and neurons. 45 percent of late-born neurons fail to migrate to their appropriate positions in the superficial cortical layers. Gross behavior deficits. Mice are small. Premature death at 2-3 months of age. Available through Jie Shen Wines-Samuelson et al., 2005 No
B6.129S7-Dp(16Lipi-Zbtb21)1Yey/J C57BL/6J A 22.9Mb duplication extending from the Lipi gene to the Zbtb21 gene on mouse chromosome 16 was generated in mouse ES cells using Cre/loxP-mediated chromosome engineering. The desired ES cell clones were injected into C57BL/6J-Tyrc-Brd blastocysts to generate chimeric mice, and these were bred to establish the B6.129S7-Dp(16Lipi-Zbtb21)1Yey/J (Dp(16)1Yey/+) mouse strain. The duplicated region includes 115 genes, including App, which are orthologous to human chromosome 21 (Hsa21), covering about 65 percent of the chromosome. Multi-transgene Down's Syndrome, Alzheimer's Disease Neuronal loss in the entorhinal cortex, locus coeruleus, and the basal forebrain magnocellular complex; increased tau pathology and increased astrocyte and microglia levels. Impairments in contextual memory, spatial learning, novel object recognition memory, and vocalizations. Altered motor coordination, sleep patterns, hearing, and vocalizations. Also, cardiopulmonary, craniofacial, skeletal, reproductive, immunological, and metabolic anomalies.  Available from The Jackson Lab: Strain 013530. Li et al., 2007 Yes
B6.129P2-Dp(16Lipi-Zbtb21)1TybEmcf/J C57BL/6J LoxP sites were inserted proximal to the Lipi gene and distal to the Zbtb21 gene in HM-1 ES cells (23Mb duplication covering about 65% of Hsa21). Cre recombinase was transiently expressed in double-targeted ES cells to induce recombination between the loxP sites. Targeted clones were injected into blastocysts to generate chimeric mice and these were bred to establish the model mouse strain by standard methods. Knock-In Down's Syndrome, Alzheimer's Disease No amyloid plaques. At 14 weeks, smaller and rounder brain, reduced medial prefrontal cortex and dorsal hippocampus volumes, reduced density of neurons, and increased density of microglia in the hippocampus. Altered hippocampal metabolites including glutamine and the glutamine/glutamate ratio. Reduced IB4 neurons in the DRG. Exploratory behavior is impaired at 8 weeks of age. Fear memory is impaired at 10 months. Motor function is impaired at 12-15 weeks of age. Sleep architecture is disrupted at 16-weeks of age. Spatial working memory is impaired at 3-months of age. Heart, lung, hematologic, skeletal, ear, and metabolic abnormalities; many similar to those associated with Down syndrome. Available from the Jackson Lab: Strain 037183 and the European Mutant Mouse Archive EM:10557. Lana-Elola et al., 2016 Yes
C57BL/6J.129P2-Dp(16Lipi-Hunk)9TybEmcf/TybH C57BL/6J In HM-1 ES cells, LoxP sites were inserted proximal to the Lipi gene and distal to the Hunk gene in chromosome 16, the mouse ortholog of human chromosome 21. Cre recombinase was used to induce recombination between the loxP sites and generate a duplicated sequence. Down's Syndrome, Alzheimer's Disease Unknown. No locomotor defects as assessed by Rotarod at 12 weeks of age. Improved trabecular and cortical bone measurements, no heart defects. Available from the European Mutant Mouse Archive (EMMA) (strain ID EM:10565).
 		 Lana-Elola et al., 2016 Yes
<p>-</p>, <p>APOE2-FAD</p>, <p>APOE2 Targeted Replacement x 5xFAD</p> C57BL/6 APOE, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V APOE2 Targeted Replacement mice were crossed with the 5xFAD line. APOE: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques starting at 4 months and increasing with age. Gliosis and loss of synaptic proteins. In the Y maze and Morris water maze, E2FAD mice performed better than E4FAD mice, and were comparabile to E3FAD mice. 5xFAD mice are available through The Jackson Lab, Stock# 034840; Live. APOE2 Targeted Replacement mice are available through Taconic, Stock# 1547-F or 1547-M. Youmans et al., 2012 Yes
<p>-</p>, <p>APOE3-FAD</p>, <p>APOE3 Targeted Replacement x 5xFAD</p> C57BL/6 APOE, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V APOE3 Targeted Replacement mice were crossed with the 5xFAD line. APOE: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques starting at 4 months and increasing with age. Gliosis and loss of synaptic proteins. In the Y maze and Morris water maze E3FAD mice performed better than E4FAD mice, and were comparabile to E2FAD mice. 5xFAD mice are available through The Jackson Lab, Stock# 034840; Live. APOE3 Targeted Replacement mice are available through Taconic, Stock# 1548-F or 1548-M. Youmans et al., 2012 Yes
<p>-</p>, <p>APOE4-FAD</p>, <p>APOE4 Targeted Replacement x 5xFAD</p> C57BL/6 APOE, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V APOE4 Targeted Replacement mice were crossed with the 5xFAD line. APOE: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques starting at 4 months and increasing with age. Gliosis and loss of synaptic proteins.  Age-dependent learning and memory deficits in the Y maze and Morris water maze. 5xFAD mice are available through The Jackson Lab, Stock# 034840; Live. APOE4 Targeted Replacement mice are available through Taconic, Stock# 1549-F or 1549-M. Youmans et al., 2012 Yes
B6(C3H)-Sod1m1H/J C57BL/6J SOD1 D83G in SOD1 This mouse has a point mutation (A>G) in the endogenous murine Sod1 gene, resulting from exposure to the chemical mutagen N-ethyl-N-nitrosourea (ENU). The endogenous murine Sod1 promoter drives expression of the mutant protein, which carries a D83G missense mutation. SOD1: Other Amyotrophic Lateral Sclerosis Upper and lower motor neuron loss in specific regions (layer V of motor cortex and lumbar spinal cord). Gliosis in spinal cord. Denervation of hindlimb muscle. Progressive motor impairments, including tremor, gait abnormalities, decreased grip strength, and impaired Rotarod performance. Liver tumors, kyphosis (hunched back), reduced body weight, loss of SOD1 activity. The Jackson Lab: Stock# 020440; Cryopreserved Joyce et al., 2015 Yes
FUSd14 B6C3F1 FUS FUS Δ14 Recombinant adeno-associated virus (AAV) to express mutant human FUS in the brain. Viral injection into the ventricles of P0 pups. Human FUS driven by the cytomegalovirus enhancer/chicken β-actin promoter. cDNA encodes C-terminal truncation, which lacks exon 14, and thus the entire nuclear localization signal. FUS: Virus Frontotemporal Dementia, Amyotrophic Lateral Sclerosis Widespread neuronal cytoplasmic inclusions (NCIs) by 3 months of age. Inclusions were FUS-positive and often co-labeled with ubiquitin.  No overt neurodegeneration or reactive gliosis. No overt motor phenotypes at 3 months of age. Viral construct available through Thomas Kukar Verbeeck et al., 2012 Yes
B6N;B6J-Fustm1Emcf/H C57BL6/J FUS FUSDelta14 truncation mutation The Fus gene in C57BL6/N mouse embryonic stem cells (ESC) was modified through homologous recombination using a targeting vector designed to introduce the following changes: g.13845 A>G (mutation at splice acceptor site of intron 13); g.14230 C>T, g.14232 A>T, g.14234C>G, g.14260 A>G, and g.14266 ATTA insertion, to humanize the coding sequence of exon 15. FUS: Knock-In Amyotrophic Lateral Sclerosis Progressive (not developmental) loss of lumbar spinal motor neurons, starting by 12 months of age; partial denervation of hindlimb muscles. Mislocalization of mutant FUS from nucleus to cytoplasm. Hindlimb motor impairment by 15 months. Premature death, beginning at 19 months of age. European Mouse Mutant Archive (EM:11106) Devoy et al., 2017 Yes
<p>-</p>, <p>Fus-dNLS</p>, <p>Fus-deltaNLS</p>, <p>Fus-ΔNLS/+</p> C57Bl/6 Fus FUS ΔNLS A targeting vector encoding exons 13 and 14 of FUS followed by three stop codons and a poly A signal was inserted between exons 12 and 13 of FUS. These elements are flanked by a pair of loxP sites. Insertion of this transgene results in the exclusion of exon 15 and the NLS unless Cre-recombinase is expressed to excise the transgene. Fus: Knock-In Amyotrophic Lateral Sclerosis The spinal cord exhibited FusΔNLS mislocalization, a loss of motor neurons, and ubiquitin pathology. No impairments in grip strength or rotarod performance. Irregular walking patterns and reduced hang time on inverted grid test were observed. Altered electrical activity of the gastrocnemius or tibialis anterior muscles. Unknown. Scekic-Zahirovic et al., 2016, Scekic-Zahirovic et al., 2017 Yes
B6;SJL-Tg(Prnp-FUS*R521C)3313Ejh/J Transgene injected into B6SJL oocytes. Maintained on C57BL/6, therefore subsequent generations have a higher percentage of C57BL/6. FUS FUS R521C Transgene encoding human FUS with the R521C mutation near the C-terminus. Flag-tagged construct driven by the Syrian hamster prion protein promoter. FUS: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Robust neurodegeneration in the anterior horn of the spinal cord, including about 50% loss of neurons by end stage. Prominent microgliosis and astrogliosis in the anterior horn at end stage. Very rare cytoplasmic FUS inclusions. A variety of motor impairments from a young age, including spastic paraplegia, abnormal hindlimb clasping, gait abnormalities, and impaired performance on the Rotarod. Growth retardation, muscle atrophy, DNA damage, and RNA splicing defects. Males may be sterile. The Jackson Lab: Stock# 026406; Cryopreserved Qiu et al., 2014 Yes
<p>-</p>, <p>Gba1<sup>D409V</sup></p>, <p>9V</p>, <p>D409V</p> Gba1tm4Ggb C57BL6, but may be mixed with 129Sv or FVB depending on the cross. Gba1 This KI mouse model was generated by introducing a c.A1366T point mutation into exon 9 of the mouse Gba1 gene to create a D409V substitution in the lipid-degrading lysosomal enzyme glucocerebrosidase. Gba1: Knock-In Parkinson's Disease No neurodegeneration in the hippocampus, striatum, or substantia nigra at 12 months of age. No neuroinflammation observed at 12 months of age in the hippocampus based on GFAP and Iba-1 immunostaining. Progressive α-synuclein accumulation starting as early as 4 months of age in the forebrain and hippocampus. Memory impaired starting at 4 months in homozygous KI mice and at 9 months in D409V/null mice. Anxiety- and compulsive-like behaviors perturbed in D409V/null mice at 6 months. Gait and locomotion normal in homozygous KI mice at 8 and 12 months, but impaired gait in D409V/null mice as early as 3 months. In 24- to 28-week-old D409V/null mice, macrophages, dendritic cells, and CD3+ T cells are increased across tissues, as are cytokine levels in serum. N/A Xu et al., 2003, Sardi et al., 2011 Yes
<p>-</p>, <p>Gba D409V KI <sup>&nbsp;&nbsp;</sup></p>, <p>Gba<sup>tm2636(D427V)Arte</sup></p> C57BL/6N-Gba1tm1.1Mjff/J Mixed C57BL/6J and C57BL/6N background. Gba1 This constitutive KI model was generated by introducing a D427V point mutation into exon 10 of Gba1, which corresponds to the human D409V mutation (The Jackson Laboratory; Polinski et al., 2021). These mice also have loxP sites flanking exons 6 to 8, which allows for the possibility of Cre-lox-mediated recombination to knock-out the mutated gene segment selectively. This recombination deletes part of the GCase domain, resulting in a frameshift and a premature stop codon. Gba1: Knock-In Parkinson's Disease No deficits in dopaminergic neuron numbers in the substantia nigra pars compacta between homozygous KI mice and wild-type mice. Dopamine levels did not differ, but dopamine turnover (ratio of DOPAC and HVA to dopamine) tended to increase at older ages. Mixed findings on GFAP and Iba-1 staining across brain regions in KI mice. Motor function is largely intact in KI mice, apart from transient increases in locomotor activity and increased grip strength at 8 and 12 months, respectively. Cognitive performance was impaired at 12 months of age, but not at younger ages. Anxiety-like behavior was not affected. Ocular pathology is observed in aged homozygous KI mice, including pigment dispersion, loss of iris pigmented epithelial cells, diminished iris stroma, posterior synechia, and cataracts. Available through The Jackson Laboratory, Stock# 019106, Cryopreserved. Polinski et al., 2021 Yes
<p>-</p>, <p>Gba*L444P</p>, <p>Gba1<sup>tm1.1Eginn</sup></p>, <p>GbaL<sup>444P/L444P</sup></p>, <p>LP/LP</p> B6.129X1(C)-Gba1tm1.1Eginn/J Mixed C57BL/6NCr and C57BL/6NJ background Gba1 L444P KI mice were generated using a loxP replacement vector, resulting in the insertion of a point mutation of leucine to proline (L444P) in exon 10 of the Gba1 gene (Ginns et al., 2014). Gba1: Knock-In Parkinson's Disease No loss of dopaminergic cells in the substantia nigra at 14 months. Inconsistent results regarding α-synuclein deposition and striatal GFAP immunostaining.   No deficits in motor balance, as detected by Rotarod and balance beam tests, observed in 16-month-old L444P KI mice. Reduced levels of glycosylated GCase in brain lysates and reduced GCase enzyme activity in the liver, spleen, and brain. Gaucher cells may be present in the liver. Available through The Jackson Laboratory, Stock# 024574, Cryopreserved. Ginns et al., 2014 Yes
<p>-</p>, <p>Gba<sup>L444P</sup></p>, <p>Gba<sup>L444P/L444P</sup></p>, <p>Gba<sup>+/L444P</sup></p> B6;129S4-Gba1tm1Rlp/Mmnc C57BL/6 and 129S4/SvJae Gba1 The L444P mutation was introduced into the mouse Gba gene using the single insertion mutagenesis procedure resulting in a partial duplication of the Gba locus (Liu et al., 1998). Gba1: Knock-In Parkinson's Disease Dopaminergic neuron numbers are intact in the substantia nigra. Some alterations in soluble α-synuclein levels, but no findings of aggregation. Levels of dopamine and its metabolites are not perturbed in heterozygous KI mice. Neuroinflammation as measured by GFAP is not observed in heterozygous KI mice, but Iba1 staining may be increased in some regions. Largely no differences in motor function between heterozygous KI and wild-type mice from 3 to 24 months of age. Impaired contextual, but not cued, fear conditioning at 3 months of age in heterozygous KI mice, but no deficits in olfaction or on the novel object recognition test at 24 months of age. Homozygous KI mice are difficult to breed and require special conditions to minimize neonatal lethality. Decreased GC enzyme activity in the brain. Generally no glucosylceramide accumulation, but elevated glucosylsphingosine levels in the brain and plasma of heterozygous KI mice. Mitochondrial structure and function impaired. Available through the Mutant Mouse Regional Resource Centres (MMRRC), Stock# 000117-UNC, Cryopreserved. Liu et al., 1998 Yes
<p>-</p>, <p>APOE4 (line1)/APOE KO</p>, <p>Tg(GFAP-APOE*4)1Hol</p> B6.Cg-Apoetm1Unc Cdh18Tg(GFAP-APOE_i4)1Hol/J. Formerly: B6.Cg-Tg(GFAP-APOE_i4)1Hol Apoetm1Unc/J B6/CBA; back-crossed onto C57BL6 background APOE Transgene of human APOE4 driven by the GFAP promoter; crossed to APOE knock-out mice. APOE: Transgenic; APOE: Knock-Out Alzheimer's Disease Developing and adult mice express human APOE4 in glia and neuropil. Unknown. Mice are viable, normal in size, and do not display any gross physical or behavioral abnormalities. The Jackson Lab: Stock# 004631; Cryopreserved Sun et al., 1998 No
<p>LOAD2</p> B6.Cg-Apoetm1.1(APOE*4)Adiuj Appem#1Adiuj Trem2em1Adiuj/J C57BL/6J APOE, APP, Trem2 TREM2 R47H CRISPR/Cas9 was used to introduce the G601R, F606Y, and R609H (APP695 numbering) point mutations into the App gene of double mutant mice with a humanized APOE4 gene and the p.R47H point mutation knocked into the mouse Trem2 gene (B6(SJL)-Apoetm1.1(APOE*4)Adiuj Trem2em1Adiuj/J, Jackson Lab Stock# 028709). APOE: Knock-In; APP: Knock-In; Trem2: Knock-In Alzheimer's Disease Unknown. Unknown. The Jackson Laboratory, Stock# 030670. Live. The Jackson Laboratory Yes
<p>-</p>, <p>hAbeta-loxP-KI on mixed B6J and B6NJ</p> B6(SJL)-Apptm1.1Aduci/J mixed B6J; B6NJ APP Three point mutations were introduced into exon 14 (exon numbering according to APP695, with 16 exons) of the mouse App gene, to produce three amino acid substitutions within the Aβ sequence (amino acids 5 (G to R), 10 (F to Y) and 13 (R to H) of Aβ). Exon 14 is also flanked by loxP sites. APP: Knock-In Alzheimer's Disease Unknown. Unknown. Available February, 2019 from The Jackson Laboratory, Stock# 030898 The Jackson Laboratory Yes
<p>-</p>, <p>hAbeta-loxP-KI</p> B6(SJL)-Apptm1.1Aduci/J mixed C57BL/6J and C57BL/6NJ App Homologous recombination was used to humanize the Aβ sequence of the endogenous App gene and to add loxP sites flanking exon 14. App: Knock-In Alzheimer's Disease No amyloid plaques observed through 22 months of age. Accelerated formation of OC-immunoreactive and Periodic Acid Schiff-positive granules. Differed from wild-type mice in the contextual fear conditioning test by 10 months of age and in the novel object recognition task by 14 months. Impaired long-term potentiation by 18 months of age. Changes in gene expression that overlap those seen in sporadic AD. Available from The Jackson Laboratory (JAX Stock No. 030898). Baglietto-Vargas et al., 2021 Yes
C57B6/C3H BACE1 Transgene of human BACE1 driven by the prion protein (PrP) promoter. BACE1: Transgenic Alzheimer's Disease No evidence of Aβ deposition in single transgenic animals. Unknown. Unknown Lee et al., 2005 No
C57BL/6 J BACE1 Wild-type human BACE driven by the murine Thy1 promoter. BACE1: Transgenic Alzheimer's Disease Not observed. Unknown. Decreased levels of full-length mature APP and increased levels of C99 and C89. Human BACE mRNA 4x higher than endogenous murine BACE. Highest expression of human BACE protein in cortex and hippocampus, lowest in cerebellum. Available through Material Transfer Management at Novartis Bodendorf et al., 2002 No
B6(SJL)-Cr2tm1(CR2,CR1)How Apoetm1.1(APOE*4)Adiuj Trem2em1Adiuj/J C57BL/6J Cr2, CR1, CR2, APOE, Trem2 TREM2 R47H This mutant line was generated by crossing APOE4/Trem2*R47H mice to mice in which the endogenous Cr2 gene was replaced with human CR1 and CR2 (The Jackson Laboratory Stock# 027713). Cr2: Knock-Out; CR1: Knock-In; CR2: Knock-In; APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease Unknown. Unknown. The Jackson Laboratory, Stock# 031668. Cryopreserved. The Jackson Laboratory Yes
<p>-</p>, <p>Tau-ON-hFUS-P525L</p> C57Bl/6 FUS FUS P525L Transgene encoding myc-tagged human FUS-P525L with an upstream Lox-P flanked stop sequence was inserted into the MAPT locus by homologous recombination. These mice were crossed to the Prm1-Cre line for germline recombination to remove the stop sequence, allowing transgene expression. FUS: Knock-In Amyotrophic Lateral Sclerosis Progressive loss of spinal cord motor neurons associated with muscle denervation and reduced muscle fiber diameter. Gliosis in spinal cord. Abnormal mitochondrial morphologies. Mutant FUS mislocalized to cytoplasm. Deficits in wire hang test at 360 days. Progressive denervation of hind limb muscles. Unknown. Sharma et al., 2016 Yes
<p>PrP-hFUS</p> Tg (Prnp-FUS)WT3Cshw/J C57Bl/6/SJL founder mice backcrossed to C57Bl/6 FUS Transgene expressing wild-type human FUS with an N-terminal HA-tag. The mouse prion protein promoter (PrP) drives transgene expression. FUS: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia FUS accumulation in the cytoplasm, including cytoplasmic inclusions in neurons of the brain and spinal cord. Degeneration of spinal motor neurons (~60% by end stage) with astrogliosis and microgliosis. Severe motor impairment, starting as tremor and gait abnormalities, and progressing to impaired performance on the Rotarod and reduced locomotion. Ultimately hindlimb paralysis and inability to lift the pelvis. Born at Mendelian ratios. Focal muscle atrophy and signs of denervation in hindlimb muscles. Most founder lines did not propagate the transgene. The Jackson Lab: Stock# 017916; Cryopreserved Mitchell et al., 2012 Yes
<p>-</p>, <p>Tau-ON-hFUS-R512C</p> C57Bl/6 FUS FUS R521C Transgene encoding myc-tagged human FUS-R521C with an upstream Lox-P flanked stop sequence was inserted into the MAPT locus by homologous recombination. These mice were crossed to the Prm1-Cre line for germline recombination to remove the stop sequence, allowing transgene expression. FUS: Knock-In Amyotrophic Lateral Sclerosis Progressive loss of spinal cord motor neurons associated with muscle denervation. Gliosis in spinal cord. Mutant FUS mislocalized to cytoplasm. No data. Progressive denervation of hind limb muscles. Unknown. Sharma et al., 2016 Yes
<p>-</p>, <p>HGBA L444P/Gba−/−</p>, <p>Tg human GCaseL444P</p> Gba1tm1.1Clk Tg(CAG-GBA*L483P)8Clk/Mmjax Mixed C57BL/6, 129 Sv background. GBA1, Gba1 The HGBA L444P/Gba−/− mouse carries a mutated human L444P HGBA transgene on a mouse Gba1 null (Gba−/−) background (Sanders et al., 2013). The mating scheme to achieve this genetic combination is to cross a haplodeficient Gba−/+ parent to a second Gba−/+ parent that additionally carries one copy of the HGBA L444P transgene. GBA1: Transgenic; Gba1: Knock-Out Parkinson's Disease Older mice do not show evidence of neuropathology or α-synuclein inclusions. Significant progressive elevations in central nervous system  glucosylsphingosine, but not glucosylceramide, were noted. No obvious phenotypic features noted. Lower GCase activity in the spleen, liver, and cerebrum compared to control mice. Increased levels of glucosylceramide and glucosylsphingosine in the liver and spleen. Overall health seems intact in older mice, based on the absence of splenomegaly, hepatomegaly, and hematologic abnormalities. Available through the Mutant Mouse Regional Resource Centres (MMRRC), Stock# 050598-JAX, Cryopreserved. Sanders et al., 2013 Yes
<p>-</p>, <p>HGBA N370S/Gba−/−</p>, <p>Tg human GCaseN370S</p> Gba1tm1.1Clk Tg(CAG-GBA*N409S)#Clk/Mmjax Mixed C57BL/6, 129 Sv background. GBA1, Gba1 The HGBA N370S/Gba−/− mouse carries a mutated human N370S HGBA transgene on a mouse Gba1 null (Gba−/−) background (Sanders et al., 2013). The mating scheme to achieve this genetic combination is to cross a haplodeficient Gba−/+ parent to a second Gba−/+ parent that additionally carries one copy of the HGBA N370S transgene. GBA1: Transgenic; Gba1: Knock-Out Parkinson's Disease Older transgenic mice do not show evidence of neuropathology or α-synuclein inclusions. Significant progressive elevations in central nervous system  glucosylsphingosine, but not in glucosylceramide, were noted. No obvious features noted. Drastically lower GCase activity in spleen, liver, and cerebrum compared to control mice. Increased levels of glucosylceramide and glucosylsphingosine in the liver and spleen. Overall health seems intact up to 70 weeks of age, based on the absence of splenomegaly, hepatomegaly, and hematologic abnormalities. Available through the Mutant Mouse Regional Resource Centres (MMRRC), Stock# 050597-JAX, Cryopreserved. Sanders et al., 2013 Yes
<p>-</p>, <p>PrP-PFN1-G118V</p> C57Bl/6 PFN1 PFN1 G118V Untagged human PFN1-G118V cDNA is expressed by the mouse prion promotor (PrP). PFN1: Transgenic Amyotrophic Lateral Sclerosis Motor neuron loss in the spinal cord associated with muscle denervation and atrophy. Gliosis in spinal cord. Loss of corticospinal neurons of the motor cortex. Aggregates of TDP-43 in spinal motor neurons. Progressive motor impairments. Minor hind limb posture changes begin at 120 days. Paralysis occurred on average by 165-210 days. Denervation and atrophy of the gastrocnemius muscle in the hindlimb. Available through Mahmoud Kiaei Fil et al., 2017 Yes
<p>-</p>, <p>human tau</p> B6.Cg-Mapttm1(EGFP)Klt Tg(MAPT)8cPdav/J The targeted allele was created in 129S4/SvJae-derived J1 embryonic stem cells that were subsequently injected into C57BL/6 blastocysts. The transgenic allele was generated in embryos derived from a cross between Swiss Webster and B6D2F1. Mice containing both alleles were back-crossed to C57BL/6 mice . MAPT Double mutant mice were generated by mating mice that express human tau (8c mice) (Duff et al., 2000), with tau knockout mice that have a targeted disruption of exon one of tau (Tucker et al., 2001), then back-crossed to obtain mice that are homozygous for disrupted murine MAPT while carrying the human tau transgene. MAPT: Knock-Out; MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia Age-associated tau pathology, including redistribution of tau to cell bodies and dendrites, phosphorylated tau, accumulation of aggregated paired helical filaments, and ultimately thioflavin-S positive neurofibrillary tangles. Pathology most severe in neocortex and hippocampus, and minimal in the brain stem and spinal cord. Some neuronal loss. Normal object-recognition memory and spatial learning/memory (as assessed by the Morris Water Maze) at four months, but impaired at 12 months (Polydoro et al., 2009).  General health, weight, basic reflexes, sensory responses, locomotor function, anxiety level, and gross motor function were not different from age-matched controls (Polydoro et al., 2009). The Jackson Lab: Stock# 005491; Live. Scantox Neuro offers research services with this line. Andorfer et al., 2003 Yes
<p>-</p>, <p>CaMKII-tTA/TRE-hTau-A152T</p> C57BL/6-Tg(tetO-MAPT*A152T)L1Lms/J C59Bl/6J MAPT MAPT A152T These bigenic mice use the CaMKIIα promoter to drive expression of tetracycline transactivator (tTA) in forebrain neurons. The responder transgene is the 1N4R isoform of human tau with the A152T mutation. Expression is constitutive unless suppressed by doxycycline. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy Tangles or dense tau inclusions not observed. Abnormal accumulations of soluble tau. Age-dependent neuronal loss was observed in the hippocampus. Age-dependent learning and memory deficits in the Morris water maze. Nest building impaired. Social interaction, anxiety, exploratory behavior, and motor functions were normal. Increase in basal synaptic activity and epileptiform spikes. Life span normal. Available as single transgenics: The Jackson Lab Stock# 028979 (cyropreserved) and Stock# 007004 (live) Maeda et al., 2016 Yes
<p>hTau40-AT</p>, <p>Ala152T-Tau</p>, <p>A152T-Tau</p>, <p>Tau/A152T</p> C57BL/6 MAPT MAPT A152T Human full-length tau (hTau40) isoform 2N4R with the A152T mutation expressed under the Thy1.2 promotor is located in the ROSA26 locus. MAPT: Knock-In Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy Tangles in hippocampus, cortex, and spinal cord at 3 months with age-dependent increases. Tau hyperphosphorylation, conformation changes, and mislocalization observed. Age-dependent loss of synapses. Age-dependent learning and memory deficits in the Morris water maze. Motor functions normal. Increase in basal synaptic transmission. Available through Eva Mandelkow Decker et al., 2016, Sydow et al., 2016 Yes
<p>-</p>, <p>Tau.P301S</p>, <p>hTAU[P301S]</p>, <p>tau[P301S]</p>, <p>Tg2541</p> Thy1-hTau.P301S (CBA.C57BL/6) CBAxC57BL/6 MAPT MAPT P301S Transgenic mice overexpressing a human tau isoform that is 383 amino acids long with four microtubule-binding repeat domains and without N-terminal inserts (4R/0N). Site-directed mutagenesis was used to introduce the P301S mutation. Transgene is under the control of the neuron-specific murine Thy-1 promoter. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy Age-dependent hyperphosphorylation of tau and conformational changes leading to neurofibrillary tanglelike pathology in the cerebral cortex, hippocampus, brain stem, and spinal cord. Neurodegeneration, especially in the spinal cord, accompanied by astrocytosis. Early motor impairment, including abnormal clasping and rotarod deficit at 4 months, with nearly complete deficit at 5 months. Deficits progress to severe paraparesis. Disinhibition and hyperactivity at 2 to 3 months. Muscle weakness, tremor. Frequent eye inflammation. Available for academic use from Michel Goedert and for commercial use from LifeArc. Also available from The Mary Lyon Centre at MRC Harwell, Archive# HAR: 011664. The CRO reMYND offers research services with this line. Allen et al., 2002 Yes
ΔNLS4; tTA/TDP-ΔNLS, TDP-43-ΔNLS, tTA/ΔNLS B6;C3-Tg(tetO-TARDBP*)4Vle/J Transgene injected into fertilized eggs from C57BL/6J x C3HeJ. TARDBP These bigenic mice use the CAMKIIα promoter to drive expression of tetracycline transactivator (tTA) in forebrain neurons. The responder transgene is wild-type human TDP-43 minus the nuclear localization signal (NLS). Human TDP-43 is expressed constitutively unless suppressed by doxycycline. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Severe neuronal loss and gliosis in the dentate gyrus and deep cortical layers. Only very rare cytoplasmic aggregates of TDP-43 despite high levels of cytosolic protein. Degeneration of the corticospinal tract, but no lower motor neuron loss or muscle atrophy. A variety of motor, cognitive, and social deficits, including abnormal clasping response, impaired coordination on the Rotarod, decreased grip strength, impaired recognition and spatial memory, and decreased social behavior. Cognitive and motor impairments largely reversible in young mice following short-term transgene suppression. Downregulation of endogenous mouse TDP-43. No change in mortality up to 7 months of age. Mendelian ratios of offspring. The Jackson Lab: Stock# 014650; Live Igaz et al., 2011 Yes
C57BL/6J-Trem2em3(TREM2)Aduci/J C57BL/6J TREM2 Mouse genomic DNA between the start codon in exon 1 and the stop codon in exon 5 of the Trem2 gene was replaced with the corresponding human genomic DNA sequence. TREM2: Knock-In Alzheimer's Disease Register interest. The Jackson Laboratory Stock No. 038103. The Jackson Laboratory Yes
C57BL/6-Trem2em2(TREM2*R47H)Aduci/J C57BL/6 TREM2 TREM2 R47H Mouse genomic DNA between the start codon in exon 1 and the stop codon in exon 5 was replaced by the corresponding human genomic DNA sequence, and the  codon at position 47 was changed from CGC (encoding arginine) to CAC (encoding histidine). TREM2: Knock-In Alzheimer's Disease Available for pre-order. The Jackson Laboratory, Stock No. 037497. The Jackson Laboratory Yes
C57BL BACE1 Transgene expressing wild-type human BACE1 driven by the mouse Thy1 promoter. BACE1: Transgenic Alzheimer's Disease Not observed. Unknown. Transgene expressed in neurons only. No change in processing of endogenous murine APP. No longer available through Michael Willem Willem et al., 2004 No
B6.Cg-Apoetm1.1(APOE*4)Adiuj Il1rapem#1Adiuj Trem2em1Adiuj/J C57BL/6J APOE, Il1rap, Trem2 TREM2 R47H CRISPR/cas9 was used to generate a knock-out mutation of the Il1rap gene of double mutant mice with a humanized APOE4 gene and the R47H point mutation knocked into the mouse Trem2 gene (B6(SJL)-Apoetm1.1(APOE*4)Adiuj Trem2em1Adiuj/J, The Jackson Laboratory Stock# 028709). APOE: Knock-In; Il1rap: Knock-Out; Trem2: Knock-In Alzheimer's Disease Unknown. Unknown. The Jackson Laboratory, Stock# 030304. Cryopreserved. The Jackson Laboratory Yes
<p>PDGF-APPSw,Ind</p>, <p>PDGF-hAPP695,751,770V171F, KM670/671NL</p>, <p>hAPPJ20</p>, <p>hAPP</p>, <p>Mucke mice</p> B6.Cg-Zbtb20Tg(PDGFB-APPSwInd)20Lms/2Mmjax C57BL/6 APP APP K670_M671delinsNL (Swedish), APP V717F (Indiana) Transgene expresses human APP with the Swedish (K670N/M671L) and Indiana (V717F) mutations under the control of the human platelet derived growth factor-β (PDGF-β) promoter. APP: Transgenic Alzheimer's Disease Age-dependent formation of Aβ plaques. Dystrophic neurites associated with plaques. No tangles. Variable cell loss. Decrease in synaptic markers and increase in complement immunoreactvity. Learning and memory deficits are age-dependent and may appear as early as 16 weeks. Hyperactivity and increased time in the open arm of the elevated plus maze than wild-type mice indicating lower levels of anxiety, but has not been universally replicated. On the C57BL/6J background hippocampal hyperexcitability was observed and cortical and hippocampal spontaneous nonconvulsive seizures. The Jackson Lab; available through the JAX MMRRC Stock# 034836-JAX; Live Mucke et al., 2000 Yes
<p>-</p>, <p>TauP301L-JNPL3</p> Tg(Prnp-MAPT*P301L)JNPL3Hlmc C57BL/6, DBA/2, SW Mixed Background MAPT MAPT P301L Transgene for human MAPT (4R0N) with the P301L mutation driven by the mouse prion promoter. MAPT: Transgenic Frontotemporal Dementia, Progressive Supranuclear Palsy, Alzheimer's Disease Age and gene-dose dependent development of neurofibrillary tangles as early as 4.5 months in homozygotes and 6.5 months in heterozyotes. Tangles and Pick-body-like inclusions in the amygdala, hypothalamus, pons, medulla, and spinal cord among other areas. Neuronal loss, especially in the spinal cord. By 10 months, 90% developed motor and behavioral disturbances including limb weakness, hunched posture, decrease in grooming and vocalization. Eye irritiation, possibily due to carrying the Pde6brd1 retinal degeneration mutation carries Pde6brd1 mutation Taconic: Stock#2508 (homozygote); #1638 (heterozygote and wild-type) has been discontinued. Lewis et al., 2000 Yes
B6(SJL)-Kif21bem1Adiuj Apoetm1.1(APOE*4)Adiuj Trem2em1Adiuj/J C57BL/6J Kif21b, APOE, Trem2 TREM2 R47H CRISPR/cas9 was used to generate a knock-in T82T mutation of the Kif21b gene of APOE4/Trem2*R47H mice—double-mutant mice with a humanized Apoe (ε4 allele) gene and the R47H point mutation knocked into the mouse Trem2 gene. Kif21b: Knock-In; APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease Unknown. Unknown. The Jackson Laboratory, Stock# 031938. Cryopreserved. The Jackson Laboratory Yes
C57BL/6-Lrrk2tm4.1Arte C57BL/6NTac LRRK2 Homologous recombination was used to introduce a mutation corresponding to human G2019S in exon 41 of the mouse LRRK2 gene. This KI line also has 2 loxP sites surrounding exon 41, allowing it to be crossed with a Cre line to remove the mutated exon in a spatially selective manner, although this feature has not been verified. LRRK2: Knock-In Parkinson's Disease Levels of phospho-substrates of LRRK2 (e.g., Rab10) are increased in the brain. Endocytosis and axonal transport defects in neurons. Cholinergic innervation density is lower in the prelimbic/infralimbic cortical areas and dorsomedial striatum, but not in the dorsal lateral geniculate nucleus in 2-6-month-old males. Microglial immunostaining is similar in the striatum and midbrain at 8 weeks Attention deficits, slower information processing speeds, and impaired goal-directed learning are evident in 2-6-month-old mice—deficits rescued by systemic administration of the acetylcholinesterase inhibitor donepezil. Cognitive flexibility and novel objective recognition similar to controls. Sleep behavior is perturbed at 8-10 months of age. Functional and structural synaptic alterations and impaired synaptic plasticity observed during development (P21) in the dorsal striatum and NAc, some of which may be transient. Impaired synaptic plasticity (LTP) in striatum present early (P21) and persists into adulthood. Available through Taconic, Cat#13940, Live. Research services with this model are available from Scantox Neuro. Matikainen-Ankney et al., 2016 Yes
<p>-</p>, <p>BAC Lrrk2-G2019S</p>, <p>FLAG-Lrrk2-G2019S</p>, <p>BAC-Lrrk2-G2019S</p>, <p>LRRK2 G2019S BAC Tg Mouse (Yue)</p> B6.Cg-Tg(Lrrk2*G2019S)2Yue/J A BAC construct was injected into B6C3 F1 oocytes. Founder line 2 was established and maintained by breeding to C57BL/6J inbred mice. LRRK2 LRRK2 G2019S A bacterial artificial chromosome (BAC) containing the entire mouse Lrrk2 gene was modified to include the G2019S mutation. The BAC (~240 kb) contained the murine Lrrk2 promoter region (~35 kb) and a FLAG-tag downstream of the start codon. LRRK2: Transgenic Parkinson's Disease Brain appears normal. No neuronal or cell death at 12 months. Impaired neurite motility and synaptic vesicle endocytosis in cultured neurons. No increase in α-synuclein or ubiquitin levels or aggregation; however, cultured neurons developed more inclusions when exposed to exogenous α-synuclein fibrils. Decreased striatal dopamine content, decreased evoked release. Apparently normal behavior. No change in activity level or motor coordination at 12 months. Motor deficits appear at 18 months. Mutant Lrrk2 protein purified from mouse brain had increased kinase activity. Age-dependent electrophysiological changes in the hippocampus including increased basal synaptic efficiency though a postsynaptic mechanism and decreased LTD. Synaptic vesicle endocytosis impaired in cultured ventral midbrain neurons. Tg mice spend less time in the REM sleep phase. Available through The Jackson Lab, Stock# 012467, cryopreserved. Li et al., 2010 Yes
<p>-</p>, <p>G2019S-LRRK2 (line 340)</p>, <p>G2019S-LRRK2 transgenic</p>, <p>LRRK2 G2019S Tg Mouse (Dawson/Moore)</p> B6;C3-Tg(PDGFB-LRRK2*G2019S)340Djmo/J Transgene introduced into C57BL/6J x C3H/HeJ embryos. Founder mice were bred with C57BL/6J mice. LRRK2 LRRK2 G2019S Transgenic mice overexpress full-length mutant human LRRK2 with the G2019S mutation. Transgene expression is driven by a hybrid CMVe-PDGFβ promoter. LRRK2: Transgenic Parkinson's Disease Age-dependent dopaminergic neuron degeneration in the substantia nigra, though reports are mixed. No reduction in striatal dopaminergic terminals or dopamine levels. Some reports of α-synuclein accumulation. Abnormal mitochondria in striatal neurons and microglia; accumulation of autophagic vacuoles. Evidence for activated striatal microglia and increased levels of CD68 and TNF-α in whole brain. Deterioration of Rotarod performance in 14- to 18-month-old mice. Muscle weakness observed on the hanging wire test by 8 months of age. No change in pre-pulse inhibition of the acoustic startle reflex. Anxiety/depression-like symptoms at 10-12 months. No differences in body weight or survival. Reduced serotonin levels in the hippocampus at 10-12 months. Age-dependent increase in 5-HT1a receptors in the hippocampus, amygdala, and dorsal raphe nucleus. Available through The Jackson Laboratory, Stock# 016575, Cryopreserved. Ramonet et al., 2011 Yes
<p>-</p>, <p>Lrrk2 knockout mouse</p>, <p>LRRK2−/−</p> B6.129X1(FVB)-Lrrk2tm1.1Cai/J C57BL/6J (but may be mixed with C57BL/6N) Lrrk2 Lrrk2 KO mice were generated by Cre-mediated deletion of coding exon 2 of the Lrrk2 gene, which results in a premature stop codon in exon 3 (Lin et al., 2009). Heterozygous KO mice were intercrossed to generate homozygous KO mice (Parisiadou et al., 2009). Lrrk2: Knock-Out Parkinson's Disease No loss in the number of TH–positive cells in the substantia nigra pars compacta up to 24 months. Cerebral cortex and dorsal striatum volumes reduced at 12 months. Striatal spiny projection neurons were enlarged and the frequency of nuclear invaginations was increased at 12 months, suggesting premature aging. Dendritic morphology perturbed at 12 months. No differences between KO and wild-type mice up to 24 months on several behavioral tests, including the elevated plus maze for anxiety-like behavior, the buried treat test to measure hyposmia, the grip strength test for forelimb strength, or working memory as measured by spontaneous alternation. Older (24-month-old) mice showed deficits in motor skill learning as measured by Rotarod. Lysosomal dysregulation is observed in the striatum and kidneys of KO mice. Immune responses perturbed upon challenge with a pathogen. Available through The Jackson Laboratory, Stock# 012453, Cryopreserved or frozen embryo. Parisiadou et al., 2009 Yes
<p>-</p>, <p>LRRK2 R1441C knock-in</p>, <p>R1441C KI</p>, <p>RC KI</p>, <p>Lrrk2 R1441C-KI</p> B6.Cg-Lrrk2tm1.1Shn/J The mutant colony was established in B6/129 F1 mice, but backcrossed to C57BL/6J wild-type mice for at least 12 generations. LRRK2 The KI mouse model was generated by homologous recombination in (C57BL/6×129)F1-derived embryonic stem cells. A 1.7-kb DNA fragment containing the R1441C missense mutation was electroporated using site-directed mutagenesis into the GTPase domain of exon 31 of the Lrrk2 locus. The colony was established in B6/129 mice, but backcrossed to C57BL/6J wild-type mice for at least 12 generations. LRRK2: Knock-In Parkinson's Disease No loss of dopaminergic (TH+) neurons in the substantia nigra pars compacta at 12 and 22 months. No loss of TH-immunoreactive neurons in the locus coeruleus. Basal levels of striatal dopamine, DOPAC, and HVA were comparable between KI and wild-type mice at 3, 12, and 23 months. However, evoked dopamine release in the striatum was reduced in adult heterozygous KI mice. Acoustic startle reflex equal to wild-type mice at 12 months of age. Motor learning impaired upon antagonism of dopamine receptors (D1 and D2). Intracellular protein transport impaired. PKA activity is elevated in the striatum. Ciliation in striatal cholinergic neurons is decreased and primary cilia formation is perturbed in the somatosensory cortex. Available through The Jackson Laboratory, Stock# 009346, Cryopreserved or frozen embryo. Tong et al., 2009 Yes
<p>-</p>, <p>R26-LRRK2; R26-LRRK2<sup>+/+</sup></p>, <p>R26-LRRK2<sup>+/+</sup>/DAT-Cre mice</p>, <p>ROSA26-LRRK2(R1441C)</p>, <p>R1441C LRRK2 Tg Mouse (Moore)</p> STOCK Gt(ROSA)26Sortm1(LRRK2*R1441C)Djmo/J R26-LRRK2 mice were generated from 129/SvJ ES cells microinjected into C57Bl/6J mouse blastocysts. Chimeras were bred with C57Bl/6J mice and maintained on a mixed genetic background (129/SvJ and C57Bl/6J). BAC-DAT-iCRE mice were maintained on a C57Bl/6J background. LRRK2 LRRK2 R1441C Full-length human LRRK2 with the R1441C mutation was targeted to the endogenous ROSA26 locus by homologous recombination. Cre-mediated excision of the transcriptional termination sequence allows for transgene expression. The Cre line expressed Cre-recombinase driven by the dopamine transporter (DAT) promoter derived from a BAC construct containing the entire mouse DAT (slc6) gene. LRRK2: Transgenic Parkinson's Disease No neurodegeneration in the brain. No proteinaceous inclusions of α-synuclein, ubiquitin, or tau. No reactive gliosis. No change in dopamine levels. Subtle morphological abnormalities in dopaminergic and non-dopaminergic neuronal nuclei, including altered nuclear envelope. No overt behavioral differences. Activity levels and Rotarod performance are normal into advanced age. Fertile. Normal survival. No overt olfactory deficits. Available through The Jackson Laboratory, Stock# 022793, Cryopreserved or frozen embryo. Tsika et al., 2014 Yes
<p>-</p>, <p>WT-OX</p>, <p>LRRK2 WT BAC</p>, <p>WT LRRK2 Mouse (BAC Tg)</p>, <p>WT LRRK2 BAC Tg Mouse (Li)</p> FVB/N-Tg(LRRK2)1Cjli/J BAC injected into fertilized FVB zygotes. Founder mice bred with FVB/N inbred mice for many generations, and then with FVB/NJ inbred mice. LRRK2 A 188 kb human bacterial artificial chromosome (BAC) containing the entire human LRRK2 gene, with 29 kb upstream and 42 kb downstream. LRRK2: Transgenic Parkinson's Disease Overtly normal brain structure. Intact, but shorter, neurites. Motor hyperactivity at 12 months of age. Available through The Jackson Laboratory, Stock# 009610, Cryopreserved. Li et al., 2009 Yes
B6(Cg)-Tc(HSA17*)1Mdk/J C57BL/6J MAPT, MAPT-AS1, Mapt MAPT IVS10+16 C>T A 190-kb region from human chromosome 17—including MAPT (H1 haplotype) with the IVS10+16 C>T mutation in intron 10, MAPT-AS1, and the SPPL2C sequence, which is contained within MAPT-AS1—replaced a 157-kb region on mouse chromosome 11 between, but not including, Crhr1 and Kansl1. MAPT: Knock-In; MAPT-AS1: Knock-In; Mapt: Knock-Out Frontotemporal Dementia Unknown. Unknown. Unknown. Available from The Jackson Laboratory, Stock No. 036664. Benzow et al., 2024 Yes
B6J.B6N-Tc(HSA17)2Mdk/J C57BL/6J MAPT, MAPT-AS1, Mapt A 190-kb region from human chromosome 17—including MAPT (H1 haplotype), MAPT-AS1, and the SPPL2C sequence, which is contained within MAPT-AS1—replaced a 157-kb region on mouse chromosome 11 between, but not including, Crhr1 and Kansl1. MAPT: Knock-In; MAPT-AS1: Knock-In; Mapt: Knock-Out Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy Unknown. Unknown. Available from The Jackson Laboratory, Stock No. 035398. Benzow et al., 2024 Yes
B6J.B6N-Tc(HSA17*N279K)1Mdk/J C57BL/6J MAPT, MAPT-AS1, Mapt MAPT N279K A 190-kb region from human chromosome 17—including MAPT (H1 haplotype) with the N279K mutation, MAPT-AS1, and the SPPL2C sequence, which is contained within MAPT-AS1—replaced a 157-kb region on mouse chromosome 11 between, but not including, Crhr1 and Kansl1. MAPT: Knock-In; MAPT-AS1: Knock-In; Mapt: Knock-Out Frontotemporal Dementia Unknown. Unknown. Available from The Jackson Laboratory, Stock No. 035794. Benzow et al., 2024 Yes
B6J.B6N-Tc(HSA17*P301L)1Mdk/J C57BL/6J MAPT, MAPT-AS1, Mapt MAPT P301L A 190-kb region from human chromosome 17—including MAPT (H1 haplotype) with the P301L mutation, MAPT-AS1, and the SPPL2C sequence, which is contained within MAPT-AS1—replaced a 157-kb region on mouse chromosome 11 between, but not including, Crhr1 and Kansl1. MAPT: Knock-In; MAPT-AS1: Knock-In; Mapt: Knock-Out Frontotemporal Dementia Unknown. No overt behavioral phenotypes Unknown. Available from The Jackson Laboratory, Stock No. 037420. Benzow et al., 2024 Yes
B6J.B6N-Tc(HSA17)1Mdk/J C57BL/6J MAPT, MAPT-AS1, Mapt A 190-kb region from human chromosome 17—including MAPT (H2 haplotype), MAPT-AS1, and the SPPL2C sequence, which is contained within MAPT-AS1—replaced a 157-kb region on mouse chromosome 11 between, but not including, Crhr1 and Kansl1. MAPT: Knock-In; MAPT-AS1: Knock-In; Mapt: Knock-Out Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy Unknown. Unknown. Available from The Jackson Laboratory, Stock No. 033668. Benzow et al., 2024 Yes
<p>-</p>, <p>MAPT KI</p>, <p>hTau KI</p> C57BL/6J MAPT Homologous recombination was used to replace the entire genomic sequence of murine Mapt (from exon 1 to exon 14) with the human MAPT gene from the ATG codon of exon 1 to the 3'-untranslated region (H2 haplotype; NCBI Reference Sequence: NG_007398). MAPT: Knock-In Alzheimer's Disease, Other Tauopathy No evidence of increased neuroinflammation, neuronal death, or brain atrophy in MAPT knock-in mice, compared with wild-type mice. MAPT knock-in mice perform similarly to wild-type mice in the Y-maze test of working memory. Compared with wild-type mice, MAPT knock-in mice showed accelerated propagation of pathological tau species after AD-derived tau was injected into the mouse brain. Available through Takaomi Saido, RIKEN Center for Brain Science. Saito et al., 2019, Hashimoto et al., 2019 Yes
<p>-</p> Ndufs2tm1.1Job Slc6a3tm1.1(cre)Bkmn/SurmJ Mixed 129, C57BL/6J, C57BL/6N, and SJL background. Ndufs2fl/fl mice contain two loxP sites flanking exon 2 of the Ndufs2 gene, and DATIREScre/+ mice contain an internal ribosome entry site–linked Cre recombinase downstream (23 bp) from the stop codon of the endogenous Slc6a3 gene (The Jackson Laboratory). Conditional Knock-out Parkinson's Disease Progressive reductions in TH expression in the striatum and SN. Overt neuron loss in the SN only at older ages (>120 days). Electrophysiological measurement of SN dopaminergic neurons showed altered pacemaking activity and burst spiking. Altered expression of many neuronal genes. Loss of evoked dopamine release in the dorsolateral striatum at 30 days of age. Impaired associative learning and striatal motor learning at 30 days. Impaired rearing at 40 days. Decreased total distance travelled by 60 days. By 100 days, splayed hindlimbs, abnormal paw placement, and alterations in stride. Impaired sleep functions starting at 6 weeks. Metabolic reprogramming to a glycolytic-predominant state of mitochondria. By 20 days, mitochondria were in an oxidative phosphorylation deficit. Altered mitochondria structure, but not mitochondrial density, observed at 35 days in dopaminergic neurons of the SN. Available through The Jackson Laboratory, Stock# 036313, Live and cryopreserved. González-Rodríguez et al., 2021 Yes
B6(SJL)-Mthfrem1Adiuj Apoetm1.1(APOE*4)Adiuj Trem2em1Adiuj/J C57BL/6J Mthfr, APOE, Trem2 TREM2 R47H CRISPR/Cas9 was used to introduce the A262V mutation into the Mthfr gene of APOE4/Trem2*R47H mice—double mutant mice with a humanized APOE4 gene and the R47H point mutation knocked into the mouse Trem2 gene. Mthfr: Knock-In; APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease Unknown. Unknown. The Jackson Laboratory, Stock# 030922. Cryopreserved. The Jackson Laboratory Yes
<p>line 13</p> C57BL/6 x DBA/2F1, crossed with DBA MAPT MAPT L266V, MAPT G272V Transgene expressing human 3R tau bearing the L266V and G272V mutations under the neuronal mThy-1 promoter. MAPT: Transgenic Frontotemporal Dementia, Pick's disease, Alzheimer's Disease Accumulation of 3R tau in neurons of the cortex and hippocampus. Pick body-like tau aggregates and neuronal loss in the hippocampus and cortex. Astrogliosis, with some 3R tau in GFAP-positive astrocytes. Synapto-dendritic changes and mitochondrial pathology. Age-related memory and motor deficits as assessed by habituation to a novel environment, the Morris water maze, and the round beam test. Increased anxiety. Unknown Rockenstein et al., 2015 Yes
<p>TASD41</p>, <p>Line 41</p>, <p>hAPPSL</p>, <p>hAPP-SL</p>, <p>AβPP751</p>, <p>mThy1-hAβPP751 Swe Lon (line 41)</p>, <p>APP751SL</p>, <p>hAPPlon/swe line 41</p>, <p>APP41</p> mThy1-hAβPP751 Swe Lon C57BL/6 x DBA APP APP K670_M671delinsNL (Swedish), APP V717I (London) The transgene over-expresses the mutant human amyloid protein precursor (751 isoform), which bears both the Swedish (K670N/M671L) and the London (V717I) mutations, under the control of the murine Thy1 promoter. APP: Transgenic Alzheimer's Disease Age-dependent increases in Aβ40 and Aβ42, with Aβ42 > Aβ40. Plaques at an early age, starting at 3-6 months in the frontal cortex. At 5-7 months, size and number of plaques increased in the frontal cortex, and dense amyloid deposits appear in hippocampous, thalamus, and olfactory region. Age-associated impairment in spatial memory and learning in the water maze task and habituation in the hole-board task, with significant deficits at 6 months of age. Some gender-specific differences in open field exploration. Available through Eliezer Masliah. The CRO PsychoGenics offers research services with this line. Rockenstein et al., 2001 Yes
<p>-</p>, <p>rNLS8</p>, <p>regulatable NLS</p> B6;C3-Tg(NEFH-tTA)8Vle Tg(tetO-TARDBP*)4Vle/J NEFH-tTA mice and tetO-hTDP-43ΔNLS line 4 mice were maintained on a mixed C57BL/6J x C3HeJ background. TARDBP These bigenic mice are the progeny of NEFH-tTA transgenic mice, in which the neurofilament heavy chain promoter drives expression of tetracycline transactivator (tTA), and tetO-hTDP-43ΔNLS (line 4) mice, which express a form of human TDP-43 lacking the nuclear localization signal in a tTA-dependent manner. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Widespread cytoplasmic inclusions of TDP-43 in the brain and spinal cord. Ubiquitin-positive inclusions, loss of endogenous mouse nuclear TDP-43, cortical atrophy, motor neuron loss, astrogliosis, and NMJ denervation. A variety of motor impairments, including hindlimb clasping, fine tremor in forelimb and/or hindlimb, progressive loss of grip strength, and decline in coordinated movement and balance. Progressive decrease in body mass from a peak two weeks off dox. Atrophy of hindlimb muscles at end-stage. Premature death (median survival 10.3 weeks off dox). Available through The Jackson Lab as single transgenics: Stock# 025397 and Stock# 014650; Live. See also double transgenic Stock# 028412; Live Walker et al., 2015 Yes
<p>-</p>, <p>dNLS-FUS</p>, <p>deltaNLS-FUS</p> C57Bl/6J FUS FUS ΔNLS Transgene encoding myc-tagged human FUS with a C-terminal truncation to delete the nuclear localization signal. Expression driven by the Thy1.2 promoter. FUS: Transgenic Amyotrophic Lateral Sclerosis The motor cortex exhibited gliosis, a loss of neurons, and ΔNLS-FUS aggregates positive for ubiquitin and p62.  Progressive motor impairments by 12 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as impaired performance on the Rotarod and hanging wire test. Reduced lifespan. Available through Daisuke Ito. Shiihashi et al., 2016 Yes
<p>-</p>, <p>ΔNLS-FUS x TARDBP</p>, <p>deltaNLS-FUS x TAR4</p> C57Bl/6J FUS, TARDBP FUS ΔNLS A cross between the ΔNLS-FUS and TDP-43(WT) mice. The ΔNLS-FUS line contains a transgene expressing myc-tagged human FUS lacking the nuclear localization signal, driven by the Thy1.2 promoter. The TDP-43(WT) line contains a transgene that encodes wild-type human TARDBP, driven by the Thy-1 promoter. FUS: Transgenic; TARDBP: Transgenic Amyotrophic Lateral Sclerosis The motor cortex exhibited gliosis, a loss of neurons, and DNLS-FUS aggregates positive for ubiquitin and p62.  Progressive motor impairments by 8 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as impaired performance on the Rotarod and hanging wire test. Reduced lifespan. Available through Daisuke Ito. Shiihashi et al., 2016 Yes
Origin: C57BL/6J; backcrossed with murine APOE-null mice APOE ApoE3 minigene driven by the rat neuron-specific enolase promoter. APOE: Transgenic Alzheimer's Disease Human ApoE3 protected against the age-dependent neurodegeneration seen in APOE -/- mice. Unknown. Widespread neuronal expression of ApoE in the brain. Expression of ApoE3 protected against kainic acid-induced neuronal damage (loss of synaptophysin-positive presynaptic terminals and MAP2-positive neuronal dendrites in the neocortex and hippocampus, and a disruption of neurofilament-positive axons in the hippocampus). Available through Robert Mahley Raber et al., 1998 No
Origin: C57BL/6J; backcrossed with murine ApoE-null mice APOE The ApoE4 minigene driven by the rat neuron-specific enolase promoter. APOE: Transgenic Alzheimer's Disease Not observed. NSE-ApoE4 mice showed impairments in learning a water maze task and in vertical exploratory behavior that increased with age and seen primarily in females. Neuronal ApoE expression was widespread in the brain. Expression of ApoE4 did not protect against kainic acid-induced neuronal damage. Available through Robert Mahley Raber et al., 1998 No
JU.Tg(NSE-APP751)Cordell JU (Developed by Eric Bradford at University of California, Davis) APP Transgene expresses wild-type human APP751 isoform under the control of the rat neural-specific enolase (NSE) promoter. APP: Transgenic Alzheimer's Disease Age-dependent increase in Aβ deposits and tau immunoreactivity. Learning and memory deficits are age-dependent as assessed on spontaneous alternation in a Y maze and in the water-maze task. Extinct Quon et al., 1991 Yes
C57BL/6× DBA/2 PSEN2 PSEN2 N141I Transgene containing human PSEN2 carrying the N141I mutation driven by the neuron-specific enolase (NSE) promoter. PSEN2: Transgenic Alzheimer's Disease Not observed. Behavioral deficits in the water maze at 12 months in mice expressing mutatnt as well as wild-type PSEN2, including longer escape latencies than wild-type mice, but no difference in swimming speed. Expression of PSEN2 was higher in mice expressing mutant as well as wild-type PSEN2 compared to age-matched, non-transgenic mice. Alterations in levels of Aβ42, caspase-3 and Cox-2 proteins. Unknown Hwang et al., 2002 No
<p>-</p>, <p>Mouse model of pathological Rab5 activation</p> C57BL/6J RAB5A Mice carry a transgene encoding myc-tagged human Rab5a, under the control of a Thy-1 promoter. RAB5A: Transgenic Alzheimer's Disease Enlarged Rab5-positive endosomes, tau hyperphosphorylation, synapse loss in hippocampus, and loss of basal forebrain cholinergic neurons. When tested at 6 months of age, the performance of PA-Rab5 mice differed from wild-type controls in a novel object recognition test. Available through Ralph Nixon. Pensalfini et al., 2020 Yes
<p>-</p> B6.129S4-Prkntm1Shn/J C57BL/6J Park2 This model was generated by homologous recombination in embryonic stem cells, which were injected into mouse blastocysts. Chimeric mice were further crossed to establish germline transmission, and backcrossed to C57BL/6 for more than 20 generations. The targeted exon 3 was replaced with part of exon 3 fused in-frame to EGFP followed by a stop codon. The resulting transcript codes for the first 95 amino acids of mouse Parkin, followed by the full EGFP amino acid sequence. A transcript that skips mutant exon 3, leading to a frameshift mutation and premature termination, is also generated. Park2: Knock-Out Parkinson's Disease No loss of dopaminergic neurons in the substantia nigra. Striatal dopamine levels may be increased basally, but reduced when evoked. Striatal medium spiny neurons had reduced synaptic excitability at 6–9 months and impaired LTP and LTD at 8 weeks, but other passive and active membrane properties were unaffected. No α-synuclein inclusions or astrogliosis. Outcomes from the forced swim test, time spent investigating novel odors, latency to find buried food, the Barnes maze test, hot plate test, Morris water maze appeared unaffected. In contrast, novel object recognition was decreased at 4-5 months and reduced sociability, increased repetitive behaviors, and deficits in communication were present at 2-3 months. Mitochondrial function and autophagy are impaired. The beige-to-white adipocyte transition and thermogenic activity of brown adipose tissue are perturbed. KO mice have impaired intestinal lipid absorption. Microtubule stability is abnormal in in the dopaminergic terminals of the striatum. Immune function against bacterial infections is perturbed. Available through The Jackson Laboratory, Stock# 006582, Live and cryopreserved. Goldberg et al., 2003 Yes
<p>-</p>, <p>PARK2-Q311X</p>, <p>Parkin-Q311X(A)</p>, <p>Parkin-Q311X (line A)</p>, <p>Parkin Q311X BAC Tg Mouse (Yang)</p>, <p>Parkin Q311(X)A</p> FVB/NJ-Tg(Slc6a3-PARK2*Q311X)AXwy/J The BAC was microinjected into fertilized FVB/NJ zygotes, then bred to FVB/NJ inbred mice. Park2 Parkin Q311X Parkin-Q311X mice have bacterial artificial chromosome (BAC)-mediated expression of mutant parkin in dopaminergic neurons. The promoter and regulatory regions of the Slc6a3 gene (encoding a dopamine transporter) drive expression of parkin with the truncation mutation Q311X. The protein has an N-terminal FLAG-tag. Two copies of the transgene are integrated in tandem. Park2: Transgenic Parkinson's Disease Degeneration of dopaminergic neurons in the SN and nerve terminals in the striatum. Reduced dopamine in the striatum. Accumulation of proteinase-K resistant α-synuclein and oxidative protein damage. Dysfunction in the burst-firing pattern activity of dopaminergic SN neurons and increased expression of markers for excitotoxic damage. Late-onset hypoactivity (about 16 months of age), other modest changes in motor behavior and coordination in tests that included traversing a beam or removing adhesive. Autophagy and lysosomal dysfunction in mutant mice at 16-17 months of age. Available through The Jackson Laboratory, Stock# 009090, cryopreserved or frozen embryo. Lu et al., 2009 Yes
<p>-</p>, <p>Parkin S65A KI</p>, <p>Parkin<sup>S65A/S65A</sup></p> C57BL/6-Prkntm1.1Muqit/J C57BL/6J Park2 Park2 S65A This constitutive KI mouse model was generated by Flp-mediated homologous recombination in mouse embryonic stem cells to introduce an S65A point mutation in exon 3 of the Park2 (Parkin) gene (McWilliams et al., 2018). Park2: Knock-In Parkinson's Disease No evidence of nigrostriatal neuropathology in 18-month-old homozygous mice. Motor dysfunction on the raised balance beam by 12 months of age. No deficits in Rotarod performance or gait. Impairments in mitochondrial respiration, but not basal mitophagy, in an age-dependent manner. Available through The Jackson Laboratory, Stock# 029247, Cryopreserved. McWilliams et al., 2018 Yes
<p>-</p>, <p>hAPP695Indiana</p>, <p>elan mouse</p>, <p>PDAPP</p>, <p>PD-APP</p> C57B6 x DBA2 APP APP V717F (Indiana) A PDGF-driven human APP minigene with the V717F (Indiana) mutation. The construct contained APP introns 6-8 allowing alternative splicing of exons 7 and 8. APP: Transgenic Alzheimer's Disease Amyloid plaques in the hippocampus, cerebral cortex. Gliosis. Dystrophic neurites. Decreased synaptic and dendritic density in the hippocampus. Deficits in a variety of memory paradigms from a young age. Deficits in the radial arm maze at 3 months (before plaques), object recognition, operant learning, spatial reference memory (starting at 3-4 months), cued fear conditioning at 11 months. Alterations in sleep/wake states, thermoregulation, and motor activity.   Unknown Games et al., 1995, Rockenstein et al., 1995 Yes
APP(Swedish,Indiana), line J9, hAPPJ9, hAPPlow C57BL/6 APP APP K670_M671delinsNL (Swedish), APP V717F (Indiana) Transgene expresses human APP with the Swedish (K670N/M671L) and Indiana (V717F) mutations under the control of the human platelet derived growth factor-β (PDGF-β) promoter. APP: Transgenic Alzheimer's Disease Amyloid plaques at 8-10 months, but not at 2-4 months when deficits in synaptic transmission are observed. Approximately 20% of mice had plaques at 5-7 months, 50% at 8-10 months, and 100% by 21-25 months. Unknown. Deficits in synaptic transmission at 2-4 months, prior to amyloid deposition. Available through Lennart Mucke Hsia et al., 1999 No
<p>line I5</p> B6.Cg-Tg(PDGFB-APP)5Lms/J (C57BL/6 x DBA/2)F2 APP APP-WT driven by the human PDGF-β promoter; an APP transgene with the Indiana mutation was converted to wild-type by PCR primer modification. APP: Transgenic Alzheimer's Disease Expression of human APP in the brain especially in the neocortex and hippocampus. No plaques up to 24 months. Unknown. The Jackson Lab: Stock# 004662; Cryopreserved Mucke et al., 2000 Yes
<p>-</p>, <p>Thy1.2-PFN1<sup>C71G</sup>/Prp-PFN1<sup>C71G</sup></p> FVB/N-Tg(Prnp-PFN1*C71G)22Zxu Tg(Thy1-PFN1*C71G)67Zxu/J FVB/NJ PFN1 PFN1 C71G Human PFN1-C71G cDNA with an N-terminal V5 tag is expressed by the human Thy1.2 promotor or mouse prion promotor (Prp). The mouse is homozygous for Thy1.2-PFN1-C71G and hemizygous for Prp-PFN1-C71G. PFN1: Multi-transgene Amyotrophic Lateral Sclerosis Motor neuron loss in the spinal cord associated with muscle denervation and atrophy. Gliosis in spinal cord. No neuronal loss in the cortex but neurodegeneration in medulla. Aggregates of PFN1, ubiquitin, and p62 form in motor neurons. Progressive motor impairments. Minor gate changes start by 4 month. Paralysis occurred on average by 7 months.Progressive decrease in body weight. Progressive decrease in body weight. Available as a triple transgenic through The Jackson Lab, Stock# 028608 Yang et al., 2016 Yes
<p>-</p>, <p>Pink1<sup>-/-</sup></p>, <p>Pink1<sup>-</sup></p>, <p>Pink1-deficient mouse</p>, <p>PARK6 mouse</p>, <p>PINK1 G309D (PINK1-) KI Mouse (Auburger)</p>, <p>Pink1*G308D</p>, <p>PINK1-knockout</p> B6;129-Pink1tm1Aub/J The vector was introduced into a 129/SvEV-derived embryonic stem cell line. Resulting chimeric mice were bred and maintained on a pure 129 background. PINK1 Pink1 G309D A targeting vector was used to introduce the G309D mutation into exon 4 at the orthologous mouse locus. A floxed neomycin cassette in the inverse orientation was inserted into intron 5 via homologous recombination. PINK1: Knock-In Parkinson's Disease No neuronal loss. No Lewy bodies or α-synuclein aggregates, but α-synuclein expression change in brainstem/midbrain. Low dopamine levels. Mitochondrial dysfunction (e.g., reduced ATP, reduced respiratory activity). Increase in factors involved in Toll-like receptor signaling in the cerebellum, and increased astrocytic and microglial markers in the corticospinal tract and striatum. Reduced spontaneous locomotor activity in open-field test. No difference in strength or coordination. Electrophysiological abnormalities, including altered glutamergic activity in midbrain dopaminergic neurons and early hypersynchrony in motor cortex. Medium spiny neurons in striatal slice exhibit giant GABAergic currents. Hyperactive subthalamic nucleus neurons, indicated by spontaneous bursts instead of single spikes. Subtle alterations in gene expression in cerebellum, midbrain, and striatum. Available through The Jackson Laboratory, Stock# 013050, Cryopreserved. Gispert et al., 2009 Yes
<p>-</p>, <p>Pink1 KO</p>, <p>Pink1 knockout mouse</p>, <p>Pink1-</p>, <p>Pink1<sup>-/-</sup></p>, <p>PINK1 KO Mouse (Shen)</p> B6.129S4-Pink1tm1Shn/J Congenic C57BL/6J. The construct was introduced into 129S4/SvJae-derived J1 embryonic stem cells, which were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to generate homozygotes and then backcrossed to C57BL/6J for &gt;7 generations. Pink1 A targeting vector containing a PGK-Neo cassette was used to disrupt exons 4 through 7 of the endogenous PINK1 gene. This creates a nonsense mutation at the beginning of exon 8; truncated RNA is degraded. Pink1: Knock-Out Parkinson's Disease Normal numbers of dopaminergic neurons and tyrosine hydroxylase levels in substantia nigra at 8-9 months of age. Alterations in the dendrites of midbrain dopaminergic neurons and cultured cortical neurons. Altered shape, density, and movement of dendritic mitochondria in cultured primary neurons from embryonic mice. Reduced BDNF levels in the midbrain and cortex at 10 months. Reduced spontaneous locomotor activity and skill at 3-6 months. Modest vocalization deficits at 4-6 months. Heavier than wildtype mice at 5 months. Plasticity abnormalities: reduced LTP and absent LTD in response to high frequency stimulation; reversed by dopamine agonists. Abnormal rise in serum cytokines in response to exhaustive exercise which acutely stresses mitochondria. Cardiac hypertrophy observed at 2 and 6 months of age. Available through The Jackson Laboratory, Stock# 017946; Live. Kitada et al., 2007 Yes
<p>hAPP/hTau/hPS1</p>, <p>PLB1(Triple)</p> C57BL6 APP, MAPT, PSEN1 APP V717I (London), APP K670_M671delinsNL (Swedish), PSEN1 A246E, MAPT P301L, MAPT R406W Targeted insertion of human APP and tau sequences at the HPRT site on the X chromosome, driven by mouse CaMKII-α. Human APP (isoform 770) with the Swedish and London mutations. Human tau (isoform 2N/4R, 441 amino acids) with P301L and R406W. APP/tau-expressing animals (PLB1-double) were crossed with hPS1 (A246E) transgenic mice (Borchelt et al., 1997) to generate the triple transgenic. APP: Multi-transgene; MAPT: Multi-transgene; PSEN1: Multi-transgene Alzheimer's Disease Age-related neuropathology including intraneuronal and oligomeric Aβ accumulation and hyperphosphorylated tau in the hippocampus and cortex from six months. Minimal amyloid plaques up to 21 months. Subtle tau pathology, but no overt tangles. Cortical hypometabolism with increased metabolic activity in basal forebrain and ventral midbrain by FDG-PET/CT. Cognitive deficits in recognition memory and spatial learning emerging between five and 12 months. Impairments in hippocampal plasticity. Litter size and overall health were normal. Mice spent more time awake at six months and had fragmented sleep. Quantitative EEG showed heightened delta power during wakefulness and REM sleep. Available through Bettina Platt Platt et al., 2011 Yes
hBACE1 C57BL/6J, for at least six generations BACE1 Targeted insertion of a single copy of human BACE1 at the HPRT locus on the X chromosome. Transgene expression driven by the mouse CaMKII-α promoter. BACE1: Transgenic Alzheimer's Disease Elevated extracellular multimeric Aβ, including Aβ*56 and Aβ hexamers, in the absence of plaques. At 12 months of age, astrogliosis was observed in a region- and genotype-dependent manner, especially in the dentate gyrus, hippocampal CA1, and piriform cortex. No overt tau pathology. Largely intact motor coordination and gait (Rotarod, CatWalk). Age-associated changes in multiple measures of learning and memory. Early deficits in habituation to a novel environment and semantic-like memory (three-four months). Impaired spatial learning and long-term reference (Morris water maze) and working memory (Y-maze) at six months, distinct from reduced locomotor activity and anxiety. Breeding, litter size, and overall health are normal. Reduced body weight in knock-in animals after six months of age in males and nine months in females. Available through Bettina Platt Plucińska et al., 2014 Yes
Plcg2em1Bwef C57BL/6J Plcg2 CRISPR/Cas9 was used to introduce the P522R mutation into the endogenous mouse Plcg2 gene. Knock-in mice were bred to homozygosity. Plcg2: Knock-In Alzheimer's Disease, Dementia with Lewy Bodies, Frontotemporal Dementia Hypertrophic astrocytes in the hippocampi, revealed by GFAP immunohistochemistry. Microglial activation revealed by TSPO PET imaging. Unknown. A subset of DAM genes and genes related to Plcγ2 signaling, the neuronal cytoskeleton, and myelination are differentially expressed in the brains of knock-in mice, compared with wild-type animals. Available through Christian Haass. Takalo et al., 2020 Yes
<p>-</p>, <p>Plcg2 knock-out</p> B6(SJL)-Plcg2em2Adiuj/J C57BL/6J Plcg2 CRISPR/Cas9 was used to introduce a knock-out mutation into the mouse Plcg2 gene. Plcg2: Knock-Out Alzheimer's Disease Unknown. Unknown. Available Fall, 2018 from The Jackson Laboratory, Stock# 29910 The Jackson Laboratory Yes
B6.Cg-Apoetm1.1(APOE*4)Adiuj Plcg2em2Adiuj Trem2em1Adiuj/J C57BL/6J APOE, Plcg2, Trem2 TREM2 R47H CRISPR/Cas9 was used to introduce the p.M28L mutation (methionine to leucine at position 28) into the Plcg2 gene of double mutant mice with a humanized APOE4 gene and the p.R47H point mutation knocked into the mouse Trem2 gene (B6(SJL)-Apoetm1.1(APOE*4)Adiuj Trem2em1Adiuj/J, The Jackson Laboratory Stock# 028709). APOE: Knock-In; Plcg2: Knock-In; Trem2: Knock-In Alzheimer's Disease Unknown. Unknown. The Jackson Laboratory, Stock# 030674. Cryopreserved. The Jackson Laboratory Yes
<p>-</p>, <p>5xFAD<sup>M28L</sup></p> C57BL/6J Plcg2, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V Plcg2*M28L/APOE4/Trem2*R47H mice (JAX 030674) were backcrossed to C57BL/6J mice to remove the APOE4 sequence and Trem2 R47H mutation. The resulting Plcg2M28L mice were then intercrossed with 5xFAD (JAX 034848) to create mice homozygous for the Plcg2 M28L mutation and hemizygous for the 5xFAD APP and PSEN1 transgenes. Plcg2: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Plaque burdens in the cortex and subiculum were elevated in 5xFADM28L mice but microglia showed less interaction with plaques, compared with 5xFAD. Six-month-old 5xFADM28L and 5xFAD mice showed similar deficits in working memory, assessed in the Y-maze. Impaired synaptic function—including deficits in basal synaptic transmission and long-term potentiation—similar to 5xFAD. Differences in microglial gene expression, compared with 5xFAD. For Plcg2M28L mice, contact Andy Tsai. 5xFAD available from The Jackson Laboratory, JAX MMRRC Stock# 034848. Tsai et al., 2023 Yes
<p>-</p>, <p>Plcg2<sup>P522R</sup></p>, <p>Plcg2<sup>R522</sup></p> B6.Cg-Plcg2em1Msasn/J C57BL/6J Plcg2 CRISPR/Cas9 gene editing was used to introduce the P522R (c.1565 C>G ) mutation into the mouse Plcg2 gene in APOE4 Knock-In mice (JAX 027894). Correctly targeted mice were then backcrossed to C57BL/6J mice (JAX 000664) to remove the human APOE4 sequence. Plcg2: Knock-In Alzheimer's Disease Unknown. Unknown. Microglia in Plcg2*P522R mice are more abundant, simpler in shape, and have lower levels of the PLCγ2 substrate, PIP2, than microglia in wild-type mice. Sight decrease in number of dendritic spines in hippocampal CA1 of Plcg2*P522R mice, compared with wild-type mice. Available from The Jackson Laboratory, Stock# 029598. Maguire et al., 2021, Bevan et al. Yes
<p>-</p>, <p>5xFAD<sup>P522R</sup></p> C57BL/6J Plcg2, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V CRISPR/Cas9 gene editing was used to introduce the P522R mutation into the mouse Plcg2 gene in APOE4 Knock-In mice (JAX 027894). Correctly targeted mice were then backcrossed to C57BL/6J mice to remove the APOE4 sequence. The resulting Plcg2R522 mice (JAX 029598) were then intercrossed with 5xFAD (JAX 034848) to create mice homozygous for the Plcg2 P522R mutation and hemizygous for the 5xFAD APP and PSEN1 transgenes. Plcg2: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Plaque burdens in the cortex and subiculum were lower in 5xFADP522R mice and microglia showed increased interaction with plaques, compared with 5xFAD. The PLCγ2 P522R variant protected against deficits in the Y-maze test of working memory in 5xFAD mice. The PLCγ2 P522R variant protected against synaptic deficits in 5xFAD mice. Differences in microglial gene expression, compared with 5xFAD. Plcg2R522 available from The Jackson Laboratory, JAX Stock# 029598; 5xFAD available from The Jackson Laboratory, JAX MMRRC Stock# 034848. Tsai et al., 2023 Yes
<p>-</p>, <p>Plcg2*P522R x APP<sup>NL-G-F</sup></p>, <p>Plcg2<sup>R522</sup> x APPNL-G-F</p>, <p>App<sup>NL-G-F</sup>R522</p> B6.Cg-Plcg2em1Msasn/J x Apptm3.1Tcs/Apptm3.1Tcs C57BL/6 Plcg2, App APP K670_M671delinsNL (Swedish), APP I716F (Iberian), APP E693G (Arctic) Plcg2R522 mice (JAX 029598) were intercrossed with APPNL-G-F knock-in mice to create animals homozygous for the Plcg2 P522R mutation and the App modifications (a humanized Aβ region, and the Swedish, Iberian, and Arctic mutations linked to Alzheimer’s disease). Plcg2: Knock-In; App: Knock-In Alzheimer's Disease Sex- and region-dependent increases in plaque burden, and decreases in microglia-plaque interactions, in Plcg2*P552R x APPNL-G-F mice, compared with APPNL-G-F. Unknown. The PLCγ2 P522R variant protected against synapse loss in APPNL-G-F mice. Plcg2*P522R mice are available from The Jackson Laboratory, JAX Stock# 029598; APPNL-G-F mice are available through Takaomi Saido. Bevan et al. Yes
<p>-</p>, <p>APP(Prnp)</p>, <p>line A-2</p> B6.Cg-Tg(Prnp-APP)A-2Dbo/J C57BL/6 APP Transgene expresses human APP driven by the mouse prion protein promoter. APP: Transgenic Alzheimer's Disease Unknown. Unknown. Jackson Labs: Stock# 006006; Cryopreserved The Jackson Laboratory No
PrP-hFUS*R495X transgenic line PX78, PrP-hFUS(R495X) line PX78 B6.Cg-Tg(Prnp-FUS*R495X)78Ljh/J Construct microinjected into C57BL/6 x SJL)F2 hybrid embryos and founders bred to FVB for 4+ generations. Subsequently back-crossed at JAX to create a C57BL/6 congenic. FUS FUS R495X These mice express a mutant form of human FUS carrying a truncation mutation near the C-terminus. The transgene is driven by the mouse prion protein promoter (Prp). The mutation abrogates the nuclear localization sequence and leads to cytoplasmic mislocalization of FUS. FUS: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Cytoplasmic mislocalization of human FUS, but no cytoplasmic inclusions or signs of neuronal loss. No overt behavioral abnormalities. By 8-12 months, EMG detected hindlimb muscular abnormalities including fibrillation potentials, muscle denervation, and a reduction in the number of motor units. Congenic available through The Jackson Lab: Stock# 019728; Cryopreserved Tibshirani et al., 2015 Yes
PWT17, PrP-hFUS(WT) line PWT17 B6.Cg-Tg(Prnp-FUS)17Ljh/J Construct microinjected into C57BL/6 x SJL)F2 hybrid embryos and founders bred to FVB for 4+ generations. Subsequently back-crossed at JAX to create a C57BL/6 congenic. FUS These mice overexpress wild-type human FUS. The transgene is driven by the mouse prion protein promoter (PrP). FUS: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia No overt neuropathology. Predominantly nuclear FUS. No inclusions or over neuronal loss. No overt behavioral abnormalities prior to becoming moribund around 203 days of age. Unexplained premature lethality about 203 days of age, proceeded by less than a week of ill-health. Congenic available through The Jackson Lab: Stock #020783; Cryopreserved Tibshirani et al., 2015 Yes
<p>-</p>, <p>PS19-TREM2<sup>CV</sup></p>, <p>PS19-T2<sup>CV</sup></p> C57BL/6 MAPT, TREM2, Trem2 MAPT P301S These mice carry a human MAPT transgene with the P301S mutation linked to frontotemporal dementia and a BAC transgene encoding the common variant of human TREM2, on a mouse-Trem2-null background. MAPT: Transgenic; TREM2: Transgenic; Trem2: Knock-Out Alzheimer's Disease, Frontotemporal Dementia Brain atrophy by 9 months of age. Increased microgliosis, astrogliosis and synapse loss, compared with PS19 mice carrying TREM2 with the R47H mutation. Not known. Increased expression of pro-inflammatory cytokines and DAM (disease-associated microglia) genes, compared with PS19 mice carrying TREM2 with the R47H mutation. PS19 mice are available from The Jackson Laboratory (Stock# 008169). TREM2 mice are available through Marco Colonna. Gratuze et al., 2020 Yes
<p>-</p>, <p>PS19-T2<sup>R47H</sup></p>, <p>PS19-TREM2<sup>R47H</sup></p> C57BL/6 MAPT, TREM2, Trem2 MAPT P301S, TREM2 R47H These mice carry a human MAPT transgene with the P301S mutation linked to frontotemporal dementia and a BAC transgene encoding the R47H variant of human TREM2, on a Trem2 knockout background. MAPT: Transgenic; TREM2: Transgenic; Trem2: Knock-Out Alzheimer's Disease, Frontotemporal Dementia Decreased brain atrophy, microgliosis, astrogliosis, and synapse loss, compared with PS19 mice carrying the common variant of TREM2. Not known. Decreased expression of pro-inflammatory cytokines and DAM (disease-associated microglia) genes, compared with PS19 mice carrying the common variant of TREM2. PS19 mice are available from The Jackson Laboratory (Stock# 008169). TREM2 mice are available through Marco Colonna. Gratuze et al., 2020 Yes
Tg(Thy1-PSEN1*A246E)2Vln/0 FVB/N PSEN1 PSEN1 A246E Transgene human PSEN1 with the A246E mutation driven by the mouse Thy1 promoter. PSEN1: Transgenic Alzheimer's Disease Histologically normal up to 2 years old by hematoxylin-eosin, silver, and thioflavin-S staining. Learning and spatial memory were unaffected in the water maze test. Neither the escape latency nor escape pathway was different from PSEN1 wild-type mice at 1 and 9 months of age. Mice are more sensitive to kainic acid displaying greater KA-induced seizure activity and neuronal damage. LTP induced by a strong stimulus was not altered, but a weak stimulation at synapses between Schaeffer’s collaterals and CA1 pyramidal neurons elicited LTP only in mutant mice. No longer available through Paul van Dun Schneider et al., 2001 No
PS1cKO, PSEN1 conditional KO fPS1/fPS1;αCaMKII-Cre CaM-Cre tg mice were generated in C57BL/6J x CBA hybrid, and then back-crossed several generations to C57BL/6J. The floxed PS1 mouse was generated in C57BL/6J and 129/Sv hybrid. PSEN1 PS1 conditional KO mice with selective deletion of PSEN1 in excitatory neurons of the forebrain beginning about 1 month of age post-natally were generated by crossing a floxed PS1 mouse with a CamKII-Cre transgenic mouse. PSEN1: Conditional Knock-out Alzheimer's Disease Reduction in Aβ40 and Aβ42 peptides; accumulation of APP C-terminal fragments. Subtle but significant deficits in long-term spatial memory in the Morris water maze. Available through Jie Shen Yu et al., 2001 Yes
<p>-</p>, <p>PSEN1(M146L)</p>, <p>PS1 (M146L) line 5.1</p> B6/D2/Swe/SJL mixed background PSEN1 PSEN1 M146L (A>C) Transgene containing human PSEN1 with the M146L mutation driven by the rat PDGF-β promoter. PSEN1: Transgenic Alzheimer's Disease No abnormal pathology up to 2.5 years. Elevated Aβ2(43); no effect on Aβ40. Altered mitochondrial activity. Disregulation of calcium homeostasis. No difference from wild-type mice in the “Y” maze (alternation performance or activity) at 12-14 weeks. Elevated PSEN1 expression (2-3 fold). Medium and late after hyperpolarizations in CA3 pyramidal cells were larger compared with wild-type mice. Larger calcium responses to depolarization. Stronger synaptic potentiation of the CA3 to CA1 projection. Available through the Technology Transfer Office, Patents & Licensing, University of South Florida. The CRO PsychoGenics offers research services with this line. Duff et al., 1996 No
PSEN1(M146V) (line 8.9) Swiss Webster x B6D2F1 PSEN1 PSEN1 M146V Transgene containing human PSEN1 with the M146V mutation driven by the rat PDGF-β promoter. PSEN1: Transgenic Alzheimer's Disease No abnormal neuropathology up to 2.5 years. Elevated Aβ42(43). Altered mitochondrial activity and disregulation of calcium homeostasis. Unknown. Medium and late after hyperpolarizations in CA3 pyramidal cells were larger compared with nontransgenic or mice transgenic for wild-type PSEN1. Available through the Technology Transfer Office, Patents & Licensing, University of South Florida Duff et al., 1996 No
PS-1 P264L knock-in R1 line of the ES cells (129 mouse strain) PSEN1 PSEN1 P264L An exon replacement strategy was used to generate mouse lines carrying a targeted mutation in their endogenous presenilin-1 gene. A proline-to-leucine substitution was targeted to codon 264 in exon 8 by homologous recombination in embryonic stem (ES) cells. Cre-lox system to remove the neomycin selection cassette from the targeted gene. PSEN1: Knock-In Alzheimer's Disease Not observed. Unknown. Unknown Siman et al., 2000 No
<p>-</p>, <p>B6.PS2APP</p>, <p>TG B6.PS2APP mice (line B6.152H)</p> Tg(Thy1-APPSwe,Prnp-PSEN2*N141I)152HLaoz C57BL/6 APP, PSEN2 APP K670_M671delinsNL (Swedish), PSEN2 N141I Coinjection of two transgenes into C57/Bl/6 zygotes: Human PSEN2 gene with the N141I mutation driven by the mouse prion protein promoter and human APP751 with the Swedish mutation driven by the Thy1.2 promoter. APP: Transgenic; PSEN2: Transgenic Alzheimer's Disease Age-associated development of plaques: none at 3 months, overt Aβ deposition in the brain at approximately 6 months, with heavy plaque load in the hippocampus, frontal cortex, and subiculum at 10 months. Aβ deposits in blood vessels were sporadic, mainly in large vessels. Cerebral amyloid deposits correlate with levels of the human APP transcript at 12 months. Cognitive impariment detected by the Morris water maze at 8 and 12 months of age, but not at 3 months. Decreased survival of newborn neurons in the dentate gyrus at about 4 months. Reduced endoplasmic reticulum Ca2+ and calcium dysregulation. A strong increase in LTP and post-tetanic potentiation (PTP) in hippocampal slices of 10 month old animals compared to wild-type mice. Decreased perfusion in the occipital cortex at all ages tested (10-17 months). Available through Laurence Ozmen Ozmen et al., 2009 Yes
PS2(N141I) x APPswe , hPS2(N141I) x hAPPswe Tg(Thy1-APPSwe)71Jgr x Tg(Prnp-PSEN2*N141I)30Jgr C57BL/6, DLB/2, crossed to C57BL/6 APP, PSEN2 APP K670_M671delinsNL (Swedish), PSEN2 N141I Double transgenics created by crossing APPSwe mice (transgene containing the 751 isoform of human APP with the Swedish mutation driven by the Thy1.2 promoter) with PS2(N141I) mice (tansgene containing human PSEN2 with the N141I mutation driven by the mouse prion protein promoter). APP: Transgenic; PSEN2: Transgenic Alzheimer's Disease Rare amyloid deposits at 5 months, with consistent deposits in the subiculum and frontolateral cortices by 9 months. Plaques increase in number and distribution with time, spreading throughout the neocortex and hippocampus as well as the amygdala and thalamic and pontine nuclei. The distribution and abundance of activated microglia and astrocytes correlate with Aβ deposition. Mice develop age-associated cognitive impairment from 8 months with impaired acquisition of spatial learning in the water maze. More insoluble Aβ40 and Aβ42 than age-matched APPSwe mice at 16-18 months. Loss of metabotropic glutamate receptors (mGlu2) in certain brain regions of aged mice as demonstrated by autoradiography. Available through Laurence Ozmen Richards et al., 2003 Yes
Prp-huPS2(N141I), PS2-N141I (line 30), hPS2mut Tg(Prnp-PSEN2*N141I)30Jgr Originally generated in a B6.D2 background, then crossed into C57BL/6J. PSEN2 PSEN2 N141I Human PSEN2 gene with the N141I mutation driven by the mouse prion protein promoter. PSEN2: Transgenic Alzheimer's Disease Unknown. Unknown. Ubiquitous expression of mutant transgene. Brain homogenate from 2 week-old mice had PSEN levels 1.8-2.2 fold higher than wild-type mice. Disrupted Ca2+ homeostasis, similar to that of double transgenic PS2APP mice, including a reduction in endoplasmic reticulum Ca2+ content in cultured neurons and a generally decreased response to metabotropic agonists. Available through Laurence Ozmen Richards et al., 2003 No
<p>-</p>, <p>PS1 + APP</p>, <p>PSAPP</p>, <p>APP/PS1</p>, <p>APP/PS1 double transgenic</p> B6/D2/Swe/SJL mixed background APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1 M146L (A>C) These double transgenic mice were generated by crossing mice overexpressing human APP with the Swedish mutation driven by the hamster prion protein gene promoter (the Tg2576 model) with mice overexpressing human PSEN1 with the M146L mutation driven by the PDGF-β promoter (PSEN1(M146L), line 5.1). The two transgenes segregate independently. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Aβ accumulates in the cerebral cortex and hippocampus starting ~6 months and increasing with age. Other regions affected later. Deposition occurs in white matter,  cerebrovasculature, and grey matter in the form of diffuse and fibrillar plaques. Fibrillar deposits are associated with dystrophic neurites and GFAP-positive astrocytes at ~ 6 months with later microglial activation. Progressive impairment between 5–7 and 15–17 months in some tests of cognitive performance, but not others. No change in anxiety levels. Selective increase in brain Aβ42(43) in the double transgenics (41% increase at 6 weeks) compared to Tg2576 single transgenic, which had unchanged Aβ40 and Aβ42(43) at this age. Tg2576: Taconic (Stock #001349) and Charles River; PS1(M146L): University of South Florida Technology Transfer Office. The CRO PsychoGenics offers research services with Tg2576 and the double transgenic line. Holcomb et al., 1998 Yes
PS1/PS2 cDKO, PSEN1/PSEN2 conditional double knock-out fPS1/fPS1;αCaMKII-Cre;PS2-/- C57BL6/129 hybrid PSEN1, PSEN2 To generate forebrain-specific conditional double knockout mice lacking both PS1 and PS2 (PS cDKO) mice, floxed PS1 (fPS1), αCaMKII-Cre transgenic mice and PS2-/- mice were crossed together to obtain fPS1/fPS1;αCaMKII-Cre;PS2-/- mice. PSEN1: Conditional Knock-out; PSEN2: Knock-Out Alzheimer's Disease At 2 months the number of apoptotic neurons is elevated about 8-fold. By 6 months, about 18 percent of of cortical neurons are lost. Up-regulation of inflammatory markers and progressive astrogliosis and microgliosis in the neocortex and hippocampus. Impairments in hippocampal learning and memory as indicated by Morris water maze and contextual fear conditioning evident by 2 months and worsens with age. Increased neurogenesis in the dentate gyrus. Available through Jie Shen Saura et al., 2004 Yes
<p>-</p>, <p>PS1 conditional KO</p> B6;129P-Psen1tm1Vln/J Origin: 129P2/OlaHsd; backcrossed to C57BL/6 PSEN1 A targeting vector containing a neomycin resistance gene was inserted downstream of exon 7 of PSEN1; loxP sites were inserted on both sides of exon 7 and downstream of the neomycin resistance gene. PSEN1: Knock-Out Alzheimer's Disease No morphological abnormalities. When crossed with Cre recombinase driven by Thy1, brain levels of Aβ40 and Aβ42 decrease and C-terminal fragments of APP accumulate. When crossed with Cre recombinase driven by Thy1, no cognitive deficit in an object recognition task. When crossed with Cre recombinase driven by Thy1, LTP induction is slightly altered. The Jackson Lab: Stock# 007605; Cryopreserved Dewachter et al., 2002 No
<p>-</p>, <p>PS1<sup>-/-</sup></p>, <p>PS1-</p>, <p>PSEN1 null</p>, <p>Psen1<sup>tm1Shn</sup></p>, <p>PS1 null</p> B6.129-Psen1tm1Shn/J C57BL/6 PSEN1 A targeting construct containing a neomycin cassette was used to disrupt exons 2 and 3 of the endogenous mouse PS1 gene. PSEN1: Knock-Out Alzheimer's Disease Impaired neurogenesis. Massive neuronal loss. Hemorrhages in the CNS. Unknown. Homozygous mice die shortly after birth; heterozygous mutants are viable and fertile. Gross skeletal malformations. The Jackson Lab: Stock# 003615; Cryopreserved Shen et al., 1997 No
<p>-</p>, <p>PS1M146V KI</p>, <p>PS1M146VKI</p>, <p>The Miles W. Miller Mouse</p> B6.129-Psen1tm1Mpm/J C57BL/6 PSEN1 PSEN1 M146V Point mutations were introduced into exon 5 of the endogenous mouse PSEN1 gene altering the codons corresponding to amino acids 145 and 146 from isoleucine and methionine to valine and valine, respectively. The targeting vector contained a lox-P flanked neomycin resistance cassette and herpes simplex virus thymidine kinase genes. PSEN1: Knock-In Alzheimer's Disease Hypersensitive to kainate-induced degeneration and death of CA3, CA1 and hilar neurons. Cultured hippocampal neurons have increased vulnerability to death induced by glutamate. Disrupted calcium homeostasis. Increased oxidative stress and mitochondrial dysfunction. Unknown. Mice are viable, fertile, and normal in size. No gross physical or behavioral abnormalities. The Jackson Lab: Stock# 004193; Cryopreserved Guo et al., 1999 No
line 13, PS1(P117L) Mixed C57BL/6 and DBA/2J PSEN1 PSEN1 P117L Transgene of human PSEN1 with the P117L mutation driven by the neuron specific enolase (NSE) promoter. PSEN1: Transgenic Alzheimer's Disease No plaques or diffuse amyloid deposits at 2-3 months. Elevated generation of Aβ42. Unknown. Express human PSEN1 at 2-3x the level of endogenous murine PSEN1. Impaired neurogenesis in the hippocampus. No longer available Wen et al., 2002 No
PS1(WT), PSEN1 (wild-type) Mixed C57BL/6J, DBA/2J PSEN1 Human wild-type PSEN1 driven by neuron-specific enolase (NSE). PSEN1: Transgenic Alzheimer's Disease No pathological changes have been observed in these mice. Unknown. No longer available Wen et al., 2002 No
line G9, H163R mutant PS-1 YAC, B6-G9, PS1-YAC B6.129S4-Tg(PSEN1H163R)G9Btla/J Origin: 129S4/SvJae, backcrossed to C57BL/6 PSEN1 PSEN1 H163R A 1000 kb YAC transgene (788H12) containing the entire human PSEN1 gene with the H163R mutation. Transgene also has ~550 kb of upstream and 350 kb of downstream flanking sequences. PSEN1: Transgenic Alzheimer's Disease Elevated Aβ42 in the brain and plasma. Higher levels and earlier Aβ deposition when crossed with APP YAC line R1.40. Unknown. Alternatively spliced human PSEN1 transcripts. The Jackson Lab: Stock# 006469; Cryopreserved Lamb et al., 1999 No
<p>-</p>, <p>PS2<sup>-/-</sup></p>, <p>PSEN2 null</p>, <p>PSEN KO</p>, <p>PS2 null</p> B6.129P-Psen2tm1Bdes/J 129P2/OlaHsd derived embryonic stem cells injected into C57BL/6 blastocysts; resulting chimeric mice backcrossed to C57BL/6J PSEN2 A targeting vector containing a hygromycin resistance gene driven by the phosphoglycerate kinase promoter was used to disrupt exon 5 of PSEN2 by introducing a frame shift between exons 4 and 6. PSEN2: Knock-Out Alzheimer's Disease No gross brain abnormalities or astrogliosis. Unknown. Alveolar wall thickening, pulmonary fibrosis, mild hemorrhage in the lungs. The Jackson Lab: Stock# 005617; Cryopreserved Herreman et al., 1999 No
PWK.Cg-Tg(APPswe,PSEN1dE9)85Dbo/How PWK/PhJ APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 Mice carry two transgenes, a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9, each controlled by the mouse prion protein promoter. Transgenic mice on a congenic C57BL/6J background were backcrossed with PWK/PhJ mice for at least six generations. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques and plaque-associated gliosis by 8 months. Transgenic mice are hyperactive and aggressive. Working memory and short-term memory are intact at 7 to 8 months, as assessed by tests in the Y-maze. Available from The Jackson Laboratory, Stock #25971. Onos et al., 2019 Yes
<p>-</p>, <p>APP<sub>NLI</sub></p> 129S6FVB F1 APP APP K670_M671delinsNL (Swedish), APP V717I (London) These are bigenic mice with the CAMKII-α promoter driving expression of tetracycline transactivator (tTa) in excitatory neurons in the forebrain, and a responder transgene consisting of mutant human APP (isoform 695) carrying the Swedish and London mutations. The expression of the transgene is constitutive until suppressed by doxycycline. APP: Transgenic Alzheimer's Disease Age-associated pathology in the cerebral cortex and hippocampus starting at 8 and 10½-12½ months of age, respectively. Gliosis and hyperphosphorylated tau in the vicinity of dense-core plaques. Fibrillar oligomeric species, e.g., Aβ dimers. No transgene-related deficits seen in Morris water maze (4, 12, 21, 24, months of age) or fixed consecutive-number (23 months of age) tests. Reduced body weight at 24-27 months relative to non-Tg littermates and those expressing only tTA. Available through Karen Ashe Liu et al., 2015 Yes
<p>-</p>, <p>neuropsin-tTA x FVB-Tg(tetO-tauP301L)4510</p> 4510 mice are on an FVB background. Neuropsin-tTA mice are on a C57BL/6 background. MAPT MAPT P301L Bigenic mice made by crossing an activator line, neuropsin-tTA, with a responder line, Tg(tetO-tauP301L)4510. The neuropsin promoter drives the tetracycline transactivator (tTA) transgene preferentially in a subset of entorhinal neurons. tTA drives expression of human tau (4R0N) with the P301L mutation. Transgene expression in bigenic mice is constitutive until suppressed by doxycycline. MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease Propagating tau pathology starting in the entorhinal cortex and spreading to regions functionally connected to the EC (e.g., dentate gyrus). Neurodegeneration and axonal degeneration, first in EC and parasubiculum. Gliosis and synaptic loss. Subtle cognitive deficit in contextual fear conditioning, but not in the radial arm maze, at 16 months. Mild specific deficit in locomotor activity in the open field test. No apparent change in anxiety as assessed by the open field test. Reduced Arc induction in the hippocampus after contextual fear conditioning. Subtle differences in basal synaptic transmission with enhanced axonal excitability. Unknown. de Calignon et al., 2012 Yes
<p>-</p>, <p>rTg4510</p>, <p>rTg(tetO-TauP301L)4510</p>, <p>Tau P301L</p> 129S6.Cg-Tg(Camk2a-tTA)1Mmay/JlwsJ; Fgf14Tg(tetO-MAPT*P301L)4510Kha/J. Formerly: 129S6.Cg-Tg(Camk2a-tTA)1Mmay/JlwsJ; FVB-Tg(tetO-MAPT*P301L)#Kha/JlwsJ Mixed: 129S6 (activator) X FVB (responder) MAPT MAPT P301L Bi-transgenic mice are made by crossing an activator line, CaMKIIα-tTA, with a responder line, Tg(tetO-tauP301L)4510. The CaMKIIα promoter drives the tetracycline transactivator (tTA) transgene preferentially in forebrain neurons. tTA drives expression of human tau (4R0N) with the P301L mutation. Transgene expression in bi-transgenic mice is constitutive until suppressed by doxycycline. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia Argyrophilic tangle-like inclusions in cortex by 4 months and in hippocampus by 5.5 months. Decreased CA1 neurons (~60 percent) by 5.5 months. Gross forebrain atrophy by 10 months. The number of CA1 neurons stabilized after a brief (six to eight week) suppression of transgenic tau. Spatial memory impairments by 2.5 to 4 months. No significant motor impairment up to 6 months of age. When the transgene was suppressed with dox at 2.5 months, spatial memory improved. Homozygous mice are not viable. It should be noted that disruption of an endogenous mouse gene, caused by random insertion of the MAPT transgene, significantly contributes to the neuropathological and neurodegenerative phenotypes observed in rTg4510 mice 4510 responder line: The Jackson Lab: Stock# 015815; Activator line: The Jackson Lab: Stock# 016198. Santacruz et al., 2005, Ramsden et al., 2005, Gamache et al., 2019 Yes
Tau R406W-Prp C57BL6 x C3H, maintained in B6C3 background MAPT MAPT R406W Human tau with the R406W mutation driven by the mouse prion protein promoter. MAPT: Transgenic Frontotemporal Dementia Age-dependent increase in tau. Neurofibrillary-tangle-like pathology (filamentous intraneuronal tau aggregates), especially in the hippocampus. Neurodegeneration. Extensive gliosis in the brain and spinal cord. Progressive motor weakness with advancing age, as demonstrated by dystonic movements of the hindlimbs when lifted by the tail. Altered microtubule binding and slow axonal transport of tau. Reduced lifespan. Unknown Zhang et al., 2004 No
<p>SAMP8</p>, <p>SAMP-8</p>, <p>SAM-P/8</p>, <p>SAM-P8</p> AKR/J, suspected outbreeding to unknown line One of several related strains developed from an AKR/J inbred line with a spontaneous accelerated aging phenotype. Spontaneous Alzheimer's Disease Age-associated increase in hippocampal Aβ from 4 to 12 months, but no plaque-like structures by Congo red or thioflavine S. Spongiform degeneration: vacuoles of various size in the neuropil in the brain stem. Microglial cell proliferation. Degeneration of dopamine neurons in the substantia nigra and noradrenaline neurons in the locus coeruleus. Age-associated behavioral impairments including learning and memory difficulties, emotional disorders (reduced anxiety-like behavior and depressive behavior) and altered circadian rhythms of spontaneous motor activity and drinking behaviours. Envigo (formerly Harlan): SAMP8-TaHsd Yagi et al., 1988 No
B6(SJL)-Apoetm1.1(APOE*4)Adiuj Snx1em1Adiuj Trem2em1Adiuj/J C57BL/6J Snx1, APOE, Trem2 TREM2 R47H CRISPR/cas9 was used to generate a D465N mutation in the Snx1 gene of APOE4/Trem2*R47H mice—double-mutant mice with a humanized Apoe (ε4 allele) gene and the R47H point mutation knocked into the mouse Trem2 gene. Snx1: Knock-In; APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease Unknown. Unknown. The Jackson Laboratory, Stock# 031942. Cryopreserved. The Jackson Laboratory Yes
line 29, SOD1 (G37R) (hybrid background), G37R(29) SOD1, SOD1 G37R C57BL/6J x C3H/HeJ)F2 SOD1 SOD1 G37R Transgene carrying a 12kb DNA fragment encoding human SOD1 with the G37R mutation. Transgene driven by the human SOD1 promoter. SOD1: Transgenic Amyotrophic Lateral Sclerosis Degeneration of motor neurons in the spinal cord and brainstem characterized by extensive vacuolization. Astrogliosis. Wallerian degeneration of large myelinated axons. No overt upper motor neuron loss. Progressive motor impairment, beginning with reduced spontaneous movement, then tremors, limb weakness, poor grooming, and muscle wasting. Eventual paralysis of hindlimbs. Elevated dismutase activity in the brain and spinal cord (~7-fold). Unknown Wong et al., 1995 Yes
<p>-</p>, <p>SOD1 (G85R) (line 148)</p> Transgene injected into hybrid (C57BL/6J x C3H/HeJ)F2 embryos. SOD1 These transgenic mice express human SOD1 with the G85R substitution. 12 kb DNA sequence under the control of the human promoter and regulatory elements. SOD1: Transgenic Amyotrophic Lateral Sclerosis Degeneration of lower motor neurons, especially large-caliber axons, but also loss of motor neurons in the ventral horn. Extensive glial pathology in the spinal cord, including astrogliosis and microgliosis. Abundant SOD1 inclusions in astrocytes. Progressive motor impairment generally starting around 8 months of age with reduced grip strength in one hindlimb, rapidly spreading to other limbs and leading to paralysis. Unknown status of the hybrid line. A congenic line is available through The Jackson Lab: Stock# 008248; Cryopreserved Bruijn et al., 1997 Yes
<p>G1H</p>, <p>High-copy SOD1-G93A</p>, <p>B6SJL.SOD1-G93A</p>, <p>Tg(hSOD1-G93A)1GUR mice</p>, <p>Gurney mice</p> B6SJL-Tg(G93A-SOD1)1Gur/J C57Bl/6/SJL. SOD1 SOD1 G93A These transgenic mice express multiple copies of human SOD1 bearing the missense mutation G93A randomly integrated into chromosome 12 of the mouse. SOD1: Transgenic Amyotrophic Lateral Sclerosis Neuronal loss in the spinal cord (~50% loss in cervical and lumbar segments by end stage). Degeneration of upper motor neurons and brainstem nuclei. Swollen neurites, Gallyas silver-positive aggregates, vacuoles, and neuritic spheroids. Gliosis. Axonal degeneration and denervation of NMJ. Progressive motor impairment that starts as a shaking tremor. Proximal muscle weakness along with muscle atrophy, eventually leading to paralysis and death. Weight loss. The mutant SOD1 retains enzymatic activity. The Jackson Lab: Stock# 002726; Live. Scantox Neuro offers research services with this model. Gurney et al., 1994, Chiu et al., 1995 Yes
B6.Cg-Sorl1em1Adiuj/J C57BL/6J Sorl1 SORL1 A528T (SNP 13) CRISPR/Cas9 gene editing was used to introduce the A528T missense mutation and a silent mutation (R529R) into the mouse Sorl1 gene in APOE4/Trem2*R47H mice (JAX 028709). Correctly targeted mice were then backcrossed to C57BL/6J mice (JAX 000664) to remove the human APOE4 sequence and the Trem2 mutation. Sorl1: Knock-In Alzheimer's Disease Available from The Jackson Laboratory, JAX Stock# 032759; cryorecovery. The Jackson Laboratory Yes
B6(SJL)-Apoetm1.1(APOE*4)Adiuj Sorl1em1Adiuj Trem2em1Adiuj/J C57BL/6J Sorl1, APOE, Trem2 TREM2 R47H, SORL1 A528T (SNP 13), APOE C130R (ApoE4) CRISPR/cas9 was used to generate a knock-in A528T mutation of the Sorl1 gene of APOE4/Trem2*R47H mice—double-mutant mice with a humanized Apoe (ε4 allele) gene and the R47H point mutation knocked into the mouse Trem2 gene. Sorl1: Knock-In; APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease Unknown. Unknown. The Jackson Laboratory, Stock# 031940. Cryopreserved. The Jackson Laboratory Yes
<p>-</p>, <p>Rosa26<sup>TgSORL1WT</sup></p> Rosa26TgSORL1WT C57BL/6J SORL1 SORL1 cDNA downstream of the cytomegalovirus early enhancer/chicken β-actin promoter and a floxed neomycin resistance cassette with a polyA stop element (neo-R) was introduced into the murine Rosa26 locus. Cre-mediated excision of neo-R induces SORL1 overexpression. SORL1: Transgenic Alzheimer's Disease Unknown. Normal performance in the Morris Water Maze. Altered transciptome and phosphoproteome compared with wild-type mice. LTP and Morris Water Maze performance are insensitive to Aβ oligomers. Available through Thomas Willnow. Caglayan et al., 2014 Yes
<p>-</p>, <p>Sorl1 knockout</p>, <p>Sorl1<sup>-/-</sup></p>, <p>Lr11<sup>-/-</sup></p>, <p>Lr11<sup>ΔEx4</sup></p> Generated on a mixed 129SvEmcTer X C57BL/6N genetic background, subsequently backcrossed to C57BL/6J. Sorl1 The 5' region of exon 4 of the murine Sorl1 gene was replaced by a neomycin resistance cassette. The disrupted allele is expressed, and mice generate low levels of a dysfunctional SORLA protein lacking 54 amino acids within the N-terminal region of the VPS10P domain. Sorl1: Knock-Out Alzheimer's Disease Mice do not generate amyloid plaques. Disrupted nigrostriatal connectivity and thinner inner nuclear layer of the retina. Hyperactivity and reduced anxiety, compared with wild-type mice. Deficits in salt homeostasis, lowered mean arterial blood pressure, decreased fat, and increased lean body mass. Increased neuronal ERK signaling and enhanced adult neurogenesis. Available through Thomas Willnow. Andersen et al., 2005, Dodson et al., 2008 Yes
<p>-</p>, <p>hm<sup>2</sup>α-SYN-39</p>, <p>HM2</p>, <p>hm<sup>2</sup>α-SYN, human doubly mutated α-synuclein</p>, <p>A30P/A53T aSyn Mouse (Tg)</p>, <p>A30P/A53T aSyn Tg Mouse (Richfield)</p>, <p>alpha-synuclein A30P/A53T Mouse (Tg)</p>, <p>B6J(<sup>2</sup>39)</p> C57BL/6J-Tg(Th-SNCA*A30P*A53T)39Eric/J Transgene injected into C57/BL6 oocytes, then bred to C57/BL6J. SNCA SNCA A30P, SNCA A53T This model expresses a transgene encoding human α-synuclein with two mutations (A30P and A53T) driven by 9kb rat tyrosine hydroxylase (TH) promoter. SNCA: Transgenic Parkinson's Disease Progressively loss of dopaminergic neurons in the substantia nigra pars compacta, observed by 8.5 months. No α-synuclein inclusions. Morphological abnormalities in the dopaminergic system, including axonal and dendritic abnormalities, reduced dopamine concentration in the striatum. More active as young adults, then hypoactive compared to non-Tg. Also reduced motor coordination in old age as measured by the time to right from an inverted wire screen. No weight differences compared to non-Tg. Available through The Jackson Laboratory, Stock# 008239, Live. Richfield et al., 2002 Yes
<p>-</p>, <p>G2-3(A53T)</p>, <p>PrPsynA53T</p>, <p>A53TαS Tg mice (line G2-3)</p>, <p>MoPrP-Huα-Syn(A53T)</p>, <p>Hualpha-Syn(A53T)</p>, <p>A53T aSyn Tg Mouse (Lee)</p>, <p>alpha-synuclein A53T Mouse (Tg)</p> B6.Cg-2310039L15RikTg(Prnp-SNCA*A53T)23Mkle/J. Formerly: B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J Established as C3H/HeJ x C57BL6/J hybrids, then maintained by backcrossing to C57Bl6/J. SNCA SNCA A53T Transgene comprising human α-synuclein with the A53T mutation was inserted downstream of the mouse prion protein (PrP) promoter. SNCA: Transgenic Parkinson's Disease No overt neuronal loss. Alterations in dopaminergic-associated proteins in the striatum, substantia nigra, and nucleus accumbens. Region-specific neuronal accumulation of fibrillar α-synuclein, ubiquitin, and neurofilament-H, and accompanying astrocytosis. Early hyperactivity followed by severe motor impairment, manifesting as wobbling, posturing, decreased spontaneous locomotor behavior, inability to navigate the Rotarod, and ultimately paralysis and death. At 11–12 months, spatial memory impaired as assessed by the Barnes circular maze. Premature death, defects in hippocampal synaptic function. Available through The Jackson Laboratory, Stock# 006823, Live. Lee et al., 2002 Yes
<p>-</p>, <p>PAC-Tg(SNCA-A53T) <sup>+/+</sup>; Snca<sup>-/-</sup></p>, <p>dbl-PAC-Tg(SNCA<sup>A53T</sup>);Snca<sup>-/-</sup></p>, <p>A53T aSyn Tg Mouse (Nussbaum)</p>, <p>Alpha-synuclein A53T Mouse (Tg) on SNCA KO</p> FVB;129S6-Sncatm1Nbm Tg(SNCA*A53T)1Nbm Tg(SNCA*A53T)2Nbm/J The PAC transgene was injected into FVB/N oocytes and founder mice bred to FVB/N. The knockout mice were made in a 129S6/SvEvTac background. SNCA SNCA A53T In this double-transgenic model, one parental line expresses mutant human α-synuclein (A53T mutation) via a 146 kb P1 artificial chromosome (PAC) containing full-length human SNCA gene and 34 kb upstream sequence. The other line is an Snca knockout line generated by replacing exons 4 and 5 with a neomycin resistance cassette. SNCA: Transgenic; SNCA: Knock-Out Parkinson's Disease No loss of dopaminergic neurons in the substantia nigra by 18 months of age. Rare dystrophic synapses in the hippocampus at advanced age, but no Lewy body-like pathology or α-synuclein aggregation in the brain. No change in striatal dopamine concentration. Impaired performance on the Rotarod and reduced spontaneous locomotor activity in open-field test. Gastrointestinal dysfunction (e.g., reduced fecal mass, reduced colonic motility, prolonged whole-gut transit time). α-synuclein–positive aggregates in enteric nervous system. No difference in body weight. No olfactory deficits. No difference in autonomic regulation of heart rate. Available through The Jackson Laboratory, Stock #010799; Live. Kuo et al., 2010, Cabin et al., 2002 Yes
<p>-</p>, <p>Snca KO</p>, <p>Snca -/-</p>, <p>Snca KO Mouse (Nussbaum)</p>, <p>Alpha-synuclein KO Mouse</p> Inbred 129/SvEvTac background. SNCA The mouse Snca gene was disrupted using a targeting vector that replaced exons 4 and 5 with the neomycin resistance gene. SNCA: Knock-Out Parkinson's Disease No gross brain abnormalities. Electron microscopy revealed synaptic vesicle abnormalities in hippocampal neurons, i.e., fewer vesicles in the reserve pool. Behavior is largely normal. Normal performance on the Rotarod. Subtle differences in locomotor activity (e.g., less rearing) but normal overall distance travelled. Learning and memory appear intact. Possible anxiety-like phenotype. Microglial abnormalities. Reduced cardiolipin content in the brain. Some mitochondrial abnormalities. Unknown. Cabin et al., 2002 Yes
<p>-</p>, <p>Sncaflox(neo)</p>, <p>SNCAflox delta neo</p>, <p>Snca conditional knockout</p>, <p>SNCA KO Mouse (Buchman)</p>, <p>Alpha-synuclein KO Mouse (Conditional)</p> B6(Cg)-Sncatm1.1Vlb/J C57BL/6J SNCA A targeting vector containing a FRT site-flanked neomysin cassette and a loxP site was inserted downstream of exon 2 and another loxP site was inserted upstream of exon 2. Flp-mediated recombination removed the FRT-flanked neo cassette, leaving exon 2 floxed. When bred to Cre-expressing mice, the resulting offspring have the first coding exon deleted in Cre-expressing tissues. SNCA: Conditional Knock-out Parkinson's Disease No data. No data. Available through The Jackson Laboratory, Stock #025636, Live. Ninkina et al., 2015, Roman et al., 2017 Yes
<p>-</p>, <p>Prp-TDP43<sup>A315T</sup></p> B6.Cg-Tg(Prnp-TARDBP*A315T)95Balo/J C57BL/6J x CBA mice backcrossed to C57BL/6J. TARDBP TARDBP A315T This transgenic mouse expresses full-length human TARDBP with an N-terminal Flag tag and the A315T mutation. The transgene is driven by the mouse prion protein (PrP) promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis Minimal motor neuron loss in the spinal cord and cortex (but see Espejo-Porras et al., 2015 and Zhang et al., 2016). Ubiquitin-positive aggregates in upper and lower motor neurons. Rare TDP-43 aggregates. Astrocytosis in spinal cord and cortical layer V. Hyperexcitability of somatostatin interneurons. Axonal degeneration and ~ 20% loss of NMJ innervation (gel diet). Variable. Gait abnormalities, and impaired performance on the Rotarod. Also deficits in radial arm water maze, not due to deficits in swimming speed. Behavior potentially confounded by gut phenotype.  Severe dysfunction in the intestinal tract involving degeneration of neurons in the colon resulting in reduced motility though the ileocaecal area. GI obstruction is the likely cause of death unless the diet is modified with soft food or gel diet. The Jackson Lab: Stock# 010700; Live Wegorzewska et al., 2009, Hatzipetros et al., 2014 Yes
<p>-</p>, <p>Baloh’s TDP-43</p>, <p>C57BL/6-CBA TDP-43 A315T</p> The Prp-TDP43A315T transgene was introduced into oocytes from C57BL/6J x CBA mice. TARDBP TARDBP A315T Transgene encodes full-length, human, mutant TARDBP with the A315T mutation and an N-terminal Flag tag. The mouse prion protein (PrP) promoter drives transgene expression. TARDBP: Transgenic Amyotrophic Lateral Sclerosis Upper and lower motor neuron loss. Cytoplasmic aggregates of ubiquitinated proteins in motor neurons. Cortical gliosis. No cytoplasmic aggregates of TDP-43. Gait abnormalities around three months, developing into a characteristic “swimming gait” by four to five months. Born at normal Mendelian ratios. Grossly normal up to three months. Muscle pathology at end-stage, including atrophic muscle fibers. Generally milder phenotypes in females. No longer available on a C57BL/6J x CBA background Wegorzewska et al., 2009 Yes
C57BL/6J Tardbp Tardp Q331K CRISPR/Cas9 was used to introduce the p.Q331K mutation into the mouse Tardp gene. Tardbp: Knock-In Frontotemporal Dementia, Amyotrophic Lateral Sclerosis Unknown. Unknown. Available through Pietro Fratta or Abraham Acevedo-Arozena Fratta et al., 2018 Yes
<p>-</p>, <p>LCDmut</p> Tardbp M323K DBA/2J x C57BL/6J Tardbp Tardbp M323K This line was generated after screening DNA archives from two large-scale chemical mutagenesis projects (Acevedo-Arozena et al., 2008; Gondo et al., 2010) for mutations in Tardbp. Tardbp: Other Frontotemporal Dementia, Amyotrophic Lateral Sclerosis At 18 months of age, p62- and ubiquitin-positive inclusions in the ventral regions of the spinal cord, although apparently not in the cytoplasm of motor neurons. TDP-43 normally localized to the nucleus in 12-month mice. At 24 months, a 28 percent reduction in the number of motor neurons in the sciatic motor neuron pool, compared with control littermates. Grip strength in both male and female mice begins to decline at 12 months of age. By 24 months, there is a nearly 40 percent reduction in force measured in tibialis anterior muscles and a 15 percent reduction in motor units innervating the extensor digitorum muscle. Mice from original founders, on a hybrid DBA/2J x C57BL/6J background, are available from the RIKEN BioResource Center, BRC# GD000110. Fratta et al., 2018 Yes
<p>-</p>, <p>RRM2mut</p> Tardbp F210I DBA/2J x C57BL/6J Tardbp Tardp F210I This line was generated after screening DNA archives from two large-scale chemical mutagenesis projects (Acevedo-Arozena et al., 2008; Gondo et al., 2010) for mutations in Tardbp. Tardbp: Other Frontotemporal Dementia, Amyotrophic Lateral Sclerosis No spinal motor neuron loss, no p62- or ubiquitin-positive inclusions at 2 years in heterozygotes. Grip strength normal at 2 years in heterozygotes. Homozygous mutation is embryonic lethal. Muscle force, motor unit numbers normal at 2 years in heterozygotes. Mice from original founders, on a hybrid DBA/2J x C57BL/6J background, are available from the RIKEN BioResource Center, BRC# GD000108. Fratta et al., 2018 Yes
thy1-APPswe Transgene injected into C57BL/6 x C3H oocytes, some backcrossing to C57BL/6 APP APP K670_M671delinsNL (Swedish) Transgene expresses human APP (isoform 695) harboring the Swedish mutation, driven by the murine Thy-1 promoter. APP: Transgenic Alzheimer's Disease Age-related accumulation of Aβ in the hippocampus and cortex leading to plaque deposition by 12 months of age. Early gliosis and dystrophic neurites, not limited to the vicinity around plaques. Changes in synaptic morphology and number, along with increased number of lysosomes. Deficits in spatial memory prior to Aβ deposition, including deficits in the Morris water maze by 6 months Deficits in spontaneous alternation behavior in the Y maze by 12 months. No deficit in fear conditioning. No differences in body temperature, locomotor activity, or Rotarod performance, relative to non-Tg controls. Unknown Richardson et al., 2003 Yes
<p>TAS10 x TPM</p>, <p>APPswe x PS1.M1466V</p>, <p>TAS/TPM</p> TAS10 transgene originally injected into C57BL/6 x C3H oocytes, with some backcrossing to C57BL/6. TPM generated on pure C57BL/6 background. APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1 M146V This is a double transgenic model generated by crossing TAS10 mice (an APP transgenic line expressing human APP695 with the Swedish mutation) with TPM mice (a PSEN1 transgenic expressing human PSEN1 with the M146V mutation). Both transgenes are driven by the murine Thy-1 promoter. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Aβ deposits beginning at 3 months of age, with fibrillar plaques by 6 months in the cerebral cortex and hippocampus. Some vascular amyloid. Plaques surrounded by dystrophic neurites and reactive glia. No tangles or neuronal loss. Female mice have more rapid and severe amyloid pathology. Age-dependent impairment in object recognition memory starting around 6 months of age.  Unknown Howlett et al., 2004 Yes
Tau(WT) transgenic (line 264) B6C3F1 embryos, backcrossed to C57BL/6 MAPT This transgenic mouse expresses 3-repeat (3R) and 4-repeat (4R) isoforms of wild-type human tau. The minigene, driven by the mouse CAMKIIα promoter, includes intronic sequences flanking exon 10, allowing for physiological splicing of exon 10. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy No overt neuropathology even at the advanced age of 24 months. Comparable to non-Tg mice in Morris water maze tasks at 4 and 6 months of age. Available through Hiroshi Mori and Takami Tomiyama Umeda et al., 2013 No
C57BL/6 (75%) and 129/Ola (25%). MAPT A fragment of human tau (187-441 a.a.) expressed under control of the human tau promotor was inserted at the Hprt locus. MAPT: Transgenic Progressive Supranuclear Palsy, Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy Progressive tau pathology in the hippocampus, including abnormally phosphorylated and misfolded tau, mislocalized tau, and tangle-like structures. Dystrophic neurites. Impaired spatial learning and memory in the Morris water maze. Early motor impairments, including abnormal limb clasping, Rotarod deficits and decreased grip strength. Muscle fibers in the quadriceps and latissimus muscles appeared to be degenerative/regenerative. Progressive spine curvature. Unknown. Bondulich et al., 2016 Yes
B6.Cg-Tg(Thy-MAPT*)2652Gds C57BL/6J MAPT This transgenic mouse overexpresses wild-type human tau (1N4R). The Thy1.2 promoter drives high levels of transgene expression in the CNS. MAPT: Transgenic Frontotemporal Dementia, Other Tauopathy, Alzheimer's Disease Extensive pretangle pathology throughout the brain (e.g. phospho- tau) but no mature neurofibrillary tangles and only mild oligomeric tau, restricted to the CA1 region of the hippocampus. Dystrophic neurites and axonal pathology (spheroids). No overt neuronal loss. Motor deficits develop with age, including decreased grip strength and impaired Rotarod performance. Cognitive deficits, indicative of impaired spatial learning and memory, as assessed by the Barnes maze. Homozygous mice have reduced body weight, reduced fertility, and premature death. Some homozygous mice also exhibit seizure activity. The MMRRC Stock# MMRRC:036717 Wheeler et al., 2015 Yes
Tau 10 + 16 , Tau(10+16 intron mutation)Tg, line 609 B6C3F1 embryos, backcrossed to C57BL/6 MAPT MAPT IVS10+16 C>T This model expresses a tau minigene driven by the mouse CAMKIIα promoter. The minigene encodes human tau 441, including partial intronic sequences flanking exon 10 of MAPT. The intronic mutation, IVS10 +16 C>T, was introduced by site-directed mutagenesis. MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease, Other Tauopathy Aggregated tau in neurons of the entorhinal cortex, hippocampus, and cerebral cortex at advanced ages. Intraneuronal accumulation of tau oligomers in the hippocampus. Neuronal loss in the entorhinal cortex and hippocampus. Gliosis. Some hippocampal areas affected by age-related synaptic dysfunction and reduced synaptic density. Impaired spatial reference memory as measured by the Morris water maze by 6 months of age.  Human tau transcripts containing exon 10 are over-represented in the adult mouse brain, leading to elevated levels of 4R tau relative to 3R tau. Available through Hiroshi Mori and Takami Tomiyama Umeda et al., 2013 Yes
<p>-</p>, <p>Tau<sup>A152T</sup>-AAV</p> C57BL/6 MAPT MAPT A152T An adeno-associated viral (AAV1) vector encoding TauA152T under the control of the cytomegalovirus enhancer/chicken β-actin promoter was injected bilaterally into the lateral ventricles of neonatal C57BL/6 mice. MAPT: Virus Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy Neuron loss and astrogliosis were observed in the cortices of 3-month-old mice. Compared with GFP-AAV controls, TauA152T-AAV mice showed deficits in contextual and cued fear conditioning, increased hyperactivity, and decreased rearing in the open-field test, and spent more time in the open arms of the elevated plus maze. TauA152T-AAV mice also exhibited motor impairment on the Rotarod. Unknown. Carlomagno et al., 2019 Yes
<p>Transgenic caspase-cleaved tau</p> BALB/C MAPT These transgenic mice express a truncated form of human tau (0N4R) that lacks the last 20 acids of the C-terminus, thus recapitulating the tau fragment produced by caspase cleavage (TauC3). Expression in the brain is driven by the promoter of the angiogenesis inhibitor 1 associated protein 4 (BAI1-AP4) gene. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia No significant cell loss or astrogliosis in the brain. Age-dependent reduction in synaptic proteins (e.g. synaptophysin, PSD95) by 1.3 to 3 months of age. Hyperphosphorylated tau oligomers and aggregates. Learning and memory deficits by 1.3 to 3 months of age, as assessed by the Y-maze and passive avoidance tests. No significant motor impairment. Normal lifespan. Unknown Kim et al., 2016 Yes
<p>-</p>, <p>mTau-E10-KO</p> Mixed background (BALB/c x C57B1/B6 x B6D2F1) MAPT Gene-targeted deletion of exon 10 in murine tau gene. MAPT: Knock-Out Alzheimer's Disease, Frontotemporal Dementia No overt neuropathology at 12 months of age. Age-dependent deterioration of sensorimotor functions, including coordination deficits on the Rotarod and a decrease in muscle strength. No deficits in learning or memory. Humanized splicing pattern of murine tau, leading to the production of 3R tau rather than 4R tau. No anxiety phenotype. Mice are no longer available, but frozen ES cells are available through Lars Nilsson or Astrid Gumucio Gumucio et al., 2013 No
<p>"Proaggregation mutant"</p>, <p>TauΔK</p>, <p>hTau40Δ280</p> Unknown. MAPT MAPT K280del These are bigenic mice in which the TET-OFF system is used to temporally control human tau expression in the brain. Tetracycline transactivator (tTA) is downstream of the CAMKII-α promoter, driving expression in excitatory neurons in the forebrain. tTA in turn stimulates expression of the responder transgene, full-length human tau (hTau40, 2N4R) carrying the FTD-associated deletion, ΔK280. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia Abundant pre-tangle pathology, but only rare mature tangles, and only at advanced ages. Tau pathology included mislocalization of tau to the somatodendritic compartment, aggregation, and hyperphosphorylation. Unknown. Available through Eva Mandelkow. Eckermann et al., 2007 Yes
<p>-</p>, <p>Tau.P301L</p>, <p>hTau.P301L</p>, <p>Tau-4R-P301L</p>, <p>Tau(P301L)</p> Thy1-hTau.P301L FVB/N MAPT MAPT P301L These transgenic mice overexpress the human Tau-4R/2N isoform bearing the P301L mutation under the control of the neuron-specific murine Thy1 promoter. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia Pathologic hyperphosphorylation and conformational change of parenchymal tau in brain tissues starting at 7 months. Tangle-like pathology is mainly observed in the brain stem and spinal cord, and to a lesser extent in the midbrain and cerebral cortex. Age-dependent increase in total tau in CSF. Age-associated deficits in a passive avoidance task (starting at 5 months) and a novel object recognition task (starting at 9 months). At a young age (~2 months) outperforms wild-type littermates in object recognition memory. Progressive motor impairment and reduced activity, accompanied by increased clasping of hind and then forelimbs around seven months. Premature death around 8-12 months, preceded by weight loss, hyperkyphosis, reduced activity, and upper airway dysfunction. The CRO reMYND offers research services with this line.  Terwel et al., 2005 Yes
<p>-</p>, <p>Tau<sup>P301L</sup>-AAV</p> C57BL/6 MAPT MAPT P301L An adeno-associated viral (AAV1) vector encoding TauP301L under the control of the cytomegalovirus enhancer/chicken β-actin promoter was injected bilaterally into the lateral ventricles of neonatal C57BL/6 mice. MAPT: Virus Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy Neurofibrillary tangles and gliosis, but no cortical neuron loss, at 6 months of age. Hyperactivity in the open field, decreased time spent in the center of open field, more time spent in the open arms of the elevated plus maze, and deficits in cued and contextual fear conditioning at 6 months of age. Unknown. Cook et al., 2015 Yes
<p>Line PS19</p>, <p>PS19Tg</p> B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle/J (C57BL/6 x C3H)F1 MAPT MAPT P301S Transgenic line expressing mutant human tau under the direction of the mouse prion protein (Prnp) promoter. The transgene codes for tau with four microtubule-binding domains and one N-terminal insert (4R/1N). MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia Neuron loss and brain atrophy by eight to 12 months, especially in the hippocampus and spreading to the neocortex and entorhinal cortex. Neurofibrillary tangles in the neocortex, amygdala, hippocampus, brain stem, and spinal cord. Neuroinflammation with microgliosis and astrocytosis. Impairments in spatial memory and learning ability in Morris water maze. Paralysis at seven to 10 months associated with a hunched-back posture followed by feeding difficulties. About 80 percent mortality by 12 months with median survival of about nine months. Clasping and limb retraction when lifted by the tail at three months, followed by limb weakness and brain atrophy. Homozygous females do not mate. The Jackson Lab: Stock# 008169; Live. Research with this model is available from Scantox Neuro. Yoshiyama et al., 2007 Yes
<p>-</p>, <p>Triple transgenic</p>, <p>3Tg</p> B6.D2-Tg(Thy1-APPSwe, Prp-PSEN2N141I, Thy1-TauP301L) C57BL/6, DBA/2; backcrossed to C57BL/6 APP, MAPT, PSEN2 APP K670_M671delinsNL (Swedish), MAPT P301L, PSEN2 N141I PS2APP mice (line B6.152H) x tau mice (line B6.TauP301L). PS2APP were generated by co-injecting two transgenic constructs: human PSEN2 (N141I mutation) and human APP (Swedish mutation) driven by the mouse prion promoter and the mouse Thy1 promoter respectively. The transgenic TauP301L mouse (line pR5) expresses the human tau40 isoform driven by the Thy1.2 promoter. APP: Transgenic; MAPT: Transgenic; PSEN2: Transgenic Alzheimer's Disease Phosphorylated tau accumulation in the subiculum and the CA1 region of the hippocampus at 4 months. Neurofibrillary tangles in these regions as well as the amygdala. Amyloid plaques. Dystrophic neurites and neuropil threads containing abnormally phosphorylated tau. No overt neuronal loss. Impaired spatial learning in the Morris water maze at 4 months but impairment is not progressive between 4 and 12 months and appears to be independent of pathology. Cortex-specific deficiencies in oxidative phosphorylation. Loss of mitochondrial membrane potential. Reduced cortical ATP. Increased superoxide anions and ROS compared to wild-type. No differences in APP expression, APP cleavage or Aβ accumulation compared to PS2APP. Levels of ptau422 increased in an age-dependent manner, but levels of ptau231 did not. Available through Laurence Ozmen Grueninger et al., 2010 Yes
TgTauR406W, Tau R406W-CAMKII B6SJL/F1; backcrossed to C57BL/6J MAPT MAPT R406W Human 4-repeat tau cDNA with the R406W mutation containing myc and FLAG tags at N-and C-terminal ends, respectively, and driven by the CaMK-II promoter. MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease Argyrophilic and congophilic tau inclusions in neurons of the forebrain with age. Detectable with Congo red, thioflavin-S and Gallyas silver stain. Congophilic tau inclusions also in the hippocampus and amygdala. Mainly straight tau filaments. Impairments in contextual and cued fear conditioning at 16–23 months compared with wild-type littermates. No detectable sensorimotor deficits. No differences from wild-type in body weight, sensorimotor reflexes (acoustic startle response), or motor coordination (accelerating rotarod and pole tests).  Attenuation of the Schaffer collateral-evoked neural response in hippocampal slices. Decrease in prepulse inhibition. Higher mortality. Unknown Tatebayashi et al., 2002 Yes
<p>“Proaggregation mutant”</p>, <p>TauRDΔ</p>, <p>TauRD</p>, <p>TauRD/ΔK280</p>, <p>TauRDΔK</p> C57BL/6 MAPT MAPT K280del Regulatable expression of an abbreviated human tau sequence (amino acids 244-372) encompassing the four microtubule-binding repeat domains and carrying the ΔK280 mutation. Transgene is driven by the forebrain-specific CAMKIIα promoter. TET-OFF system in which the transgene is regulated by the tetracycline transactivator (tTA) and turned off by administration of doxycycline. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia Tau aggregates and tangles as early as 2-3 months after gene expression. Gallyas silver-positive neurons abundant in the entorhinal cortex and amygdala, spreading to the neocortex by 15 months. “Ballooned” neurons. Astrogliosis. Synaptic structural changes and reduced synaptic number. Hippocampal neuronal loss. Reversible learning and memory deficits in the Morris water maze and passive avoidance test. No significant motor deficit, although slight reduction in Rotarod performance. Missorting of tau into the somato-dendritic compartment. Calcium dysregulation at synaptic boutons. Deficits in synaptic plasticity, including LTP and LTD. Unknown Mocanu et al., 2008 Yes
MAPT V337M, Tg214 B6SJL/F1 MAPT MAPT V337M Human 4-repeat tau driven by the PDGF-β promoter. Tagged with myc and Flag on the N- and C-terminals respectively. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia SDS-insoluble tau aggregates in hippocampus. Degenerating neurons in the hippocampus containing phosphorylated and ubiquitinated tau aggregates with β-sheet structure. Higher overall spontaneous locomotion than non-transgenic littermates in elevated plus maze. No differences in the Morris water maze. The amount of mutant tau varied, but was generally less than one tenth of endogenous tau levels. In hippocampal slices there was attenuation of the Schaffer collateral-evoked neural response. Unknown Tanemura et al., 2002, Tanemura et al., 2001 Yes
Truncated beta-amyloid 42 C57BL6 APP Transgenic vector expresses a human N-terminally truncated Aβ sequence (3-42) fused to thyrotropin-releasing hormone. The transgene is under the control of the murine Thy1.2 regulatory sequence. The glutamate at position 3 of Aβ was mutated to glutamine to facilitate pyroglutamate formation by the enzyme glutaminyl cyclase. APP: Transgenic Alzheimer's Disease Intraneuronal accumulation of Aβ peptides in the hippocampus by 3 months and in cerebellar nuclei by 6 months. Marked gliosis in the hippocampus by 12 months. Very rare extracellular Aβ deposits. Age-dependent behavioral deficits, including working memory as assessed by the cross maze at 12 months, but not at 3 or 6 months. Early and persistent decrease in anxiety in the elevated plus maze. Comparable to wild-type in general motor coordination at 3 and 6 months as indicated by the balance-beam test, but impairment at 12 months. Available through Thomas Bayer Wittnam et al., 2012 Yes
<p>-</p>, <p>Tc(HSA21q;MAC)1Yakaz</p>, <p>B6D2F1 TcMAC21</p>, <p>DS-MAC</p>, <p>HSA21-MAC Tc</p> TcMAC21 B6/D2 (C57BL/6J (B6) x DBA/2J (D2)) TcMAC21 has a freely and stably-segregating hybrid mouse artificial chromosome (MAC) that contains a nearly complete long-arm of human chromosome 21 (Hsa21q; 34 MB including ~93 percent of protein-coding genes and ~79 percent of non-coding sequences). Multi-transgene Down's Syndrome, Alzheimer's Disease Elevated APP, Aβ40, and Aβ42 in brain at 15–24 months, but no amyloid plaque pathology. Enlarged lateral ventricles and superior colliculus, and smaller cerebellum. Learning and memory deficits. Reduced body size and weight, retrusion of the midface skeleton and mandible, congenital heart defects of septation and outflow tract, hematological abnormalities. Also, hypermetabolism, raised body temperature, hyperactive, with altered glucose and insulin biology. Available from Riken Animal Resource RBRC05796. Also available from The Jackson Laboratory #035561. Kazuki et al., 2020 Yes
Transgene injected into C3H x C57Bl/6 embryos and then crossed with C57Bl/6. TARDBP TARDBP A315T Full-length human TDP-43 with the A315T mutation introduced by site-directed mutagenesis. The transgene is driven by the endogenous human promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Cytoplasmic inclusions of TDP-43, axonal changes, gliosis, no overt neuronal loss or loss of axons. Increased levels of cytotoxic 25 kDA C-terminal fragment of TDP-43. Age-associated cognitive and motor deficits as measured by the passive avoidance test and the Rotarod. Normal lifespan and fertility. Available through Jean-Pierre Julien Swarup et al., 2011 Yes
line 23 STOCK Tg(Prnp-TARDBP*A315T)23Jlel/J Transgene injected into fertilized hybrid B6SJLF1oocytes. Founders bred with CD1 to create hybrid CD1 and B6SJLF. TARDBP TARDBP A315T Transgene encodes full-length human TDP-43 with the A315T mutation. The mouse prion protein (Prp) promoter drives transgene expression. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia No overt neuronal loss in the brain or spinal cord. Ubiquitin-positive cytoplasmic inclusions in neurons of the ventral horn and brainstem. Astrocytosis. Cytoplasmic aggregates of TDP-43 are largely absent, although some phospho-TDP-43 inclusions at end-stage. Progressive motor impairment characterized by weakness, a decline in grip strength, and reduction in stride length. Weakness was usually more pronounced in the hindlimbs. Prior to motor deficits, mice exhibit increased fat storage, decreased lean muscle mass, and larger adipocytes in white fat. The Jackson Lab: Stock# 016143; Cryopreserved Stallings et al., 2010 Yes
Transgene injected into C3H x C57Bl/6 embryos. Founders backcrossed with C57Bl/6. TARDBP TARDBP G348C Full-length human TDP-43 with the G348C mutation introduced by site-directed mutagenesis. The transgene is driven by the endogenous human TARDBP promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Cytoplasmic inclusions of TDP-43 in neurons, axonal changes, denervated NMJs, gliosis, no overt neuronal loss or loss of axons. Increased levels of cytotoxic 25 kDA C-terminal fragment of TDP-43. Age-associated cognitive and motor deficits as measured by the passive-avoidance test, the Barnes maze, and the Rotarod. Impaired recovery after crush injury to the sciatic nerve (e.g., delayed recovery of motility and reduced axon regrowth). Normal lifespan and fertility. Available through Jean-Pierre Julien Swarup et al., 2011 Yes
<p>-</p>, <p>TDP-43 M337V PrP (line 4)</p> C57BL/6-Tg(Prnp-TARDBP*M337V)4Ptrc/J Transgene injected into fertilized C57BL/6 oocytes. Founders bred with B6. TARDBP TARDBP M337V Transgene expresses full-length human TARDBP with the M337V mutation, driven by the mouse prion protein (PrP) promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia No overt neuronal death. Microgliosis and astrogliosis. Abnormal mitochondria in the form of eosinophilic aggregates in spinal motor neurons. Widespread ubiquitination and accumulation of phospho-tau. Body tremors and gait difficulties before one month of age, leading to a “dragging” gait. An inability to right themselves precipitating euthanasia around one to two months of age. Reduced brain and body weight compared with non-Tg littermates. The Jackson Lab: Stock# 017604; Cryopreserved Xu et al., 2011 Yes
Mt-TAR6/6 Transgene injected into BL6/SJL oocytes. Founders crossed to C57BL6/J. TARDBP TARDBP M337V The Thy-1.2 promoter drives expression of a transgene encoding human TARDBP with the M337V mutation. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Neuronal loss in cortical layer V motor neurons, spinal anterior horn motor neurons, CA regions of the hippocampus, and thalamic neurons. Astrogliosis and microgliosis. Diffuse cytoplasmic ubiquitin in cortical and spinal motor neurons and hippocampus, but rare overt inclusions. Deformed mitochondria and fission deficits. Progressive motor impairment, involving a hunched posture, muscle twitches, and reduced mobility. Impaired Rotarod performance. Complete paralysis and premature death. Postnatal growth retardation and weight loss. Transgene induced downregulation in endogenous TDP-43. Increased caspase-3 expression. Ultrastructural mitochondria abnormalities. Unknown Janssens et al., 2013 Yes
Transgene introduced into C57Bl6/C3H oocytes. Founders crossed to C57/Bl6 for a minimum of four generations. TARDBP TARDBP Q331K Full-length human TDP-43 with the Q331K mutation driven by the mouse prion protein (Prp) promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Age-dependent lower motor loss, gliosis, NMJ abnormalities and loss. No TDP-43 aggregates or cytoplasmic mislocalization. A variety of motor impairments starting around 3 months of age including tremor, abnormal hindlimb clasping, decreased Rotarod performance, and a later decrease in grip strength. Unknown Arnold et al., 2013 Yes
<p>-</p>, <p>TDP-43<sup>Q331K</sup> KI (Line 52)</p> C57Bl/6J Tardbp Tardp Q331K CRISPR/Cas9 mutagenesis was used to introduce a point mutation equivalent to human Q331K into the mouse Tardp gene. Tardbp: Knock-In Frontotemporal Dementia, Amyotrophic Lateral Sclerosis No TDP-43- or tau-positive inclusions. No apparent loss of upper or lower motor neurons, but 25% decrease in number of parvalbumin-positive neurons in frontal cortex. Attention deficits in a five-choice serial reaction time task, memory deficits in a novel-object-recognition task, deficits in a marble-burying task. No apparent motor impairments. Gene-expression and splicing differences, compared with wild-type mice, including upregulation of Tardp, and altered splicing of Tardp, Sort1, Mapt. Available from Jemeen Sreedharan or Robert H. Brown Jr. White et al., 2018 Yes
<p>Elliott</p>, <p>WT TDP-43 (line 4)</p> B6SJL-Tg(Prnp-TARDBP)4Jlel/J Transgene injected into B6SJLF1 oocytes. Founders crossed with CD1 mice. TARDBP Transgene expressing full-length, wild-type, human TDP-43 driven by the mouse prion protein (Prp) promoter. Transgene integrated on X chromosome. TARDBP: Transgenic Amyotrophic Lateral Sclerosis No overt neuronal loss in the brain or spinal cord.  Progressive motor impairment (variable penetrance) starting with external rotation of one hind limb followed by bilateral weakness and low muscle tone. Relatively high TDP-43 expression in skeletal muscle. Myopathy, including variable muscle fiber size and disorganization of the muscle architecture. Ubiquitin-positive inclusions in skeletal muscle cells. Status of original hybrid unknown. This model is available on a B6SJL background through The Jackson Lab: Stock# 016201; Cryopreserved Stallings et al., 2010 Yes
<p>Julien model</p>, <p>Wild-type TDP-43</p> Transgene injected into C3H x C57Bl/6 embryos. Founders crossed with C57Bl/6. TARDBP Full-length, wild-type, human TDP-43 driven by the endogenous human promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Some denervated NMJs, gliosis (microgliosis and astrogliosis), no overt neuronal loss or loss of axons. Mostly nuclear expression of TDP-43. Age-associated cognitive and motor deficits as measured by the passive avoidance test, Barnes maze, and Rotarod. Impaired recovery following crush injury to the sciatic nerve (e.g., delayed recovery of motility, reduced axon regrowth). Normal lifespan and fertility. Not available: extinct Swarup et al., 2011 Yes
<p>-</p>, <p>WT-TAR4/4</p>, <p>WT-TAR4</p> B6;SJL-Tg(Thy1-TARDBP)4Singh/J Transgene introduced into BL6/SJL oocytes. Founders crossed to C57BL6/J. TARDBP Transgene encodes wild-type human TARDBP, driven by the murine Thy-1 promoter. The transgene integrated at locus 6qB3 in the mouse genome and does not interrupt any known gene. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Neuronal loss in the brain and spinal cord, including anterior cortex, CA3 hippocampus, Purkinje cells, and spinal cord. Astrogliosis and microgliosis especially in the anterior cortex. Widespread diffuse ubiquitin in neurons of the brain and spinal cord, including cytoplasmic and nuclear inclusions, some co-labeling for TDP-43. Progressive motor impairment, starting at postnatal day 14, with an abnormal hindlimb reflex. Gait abnormalities, including reduced stride length and impaired performance on the accelerating Rotarod. Quick progression to muscle fasciculation’s and spasms, followed by paralysis and premature death. Elevated anxiety at a young age. Size and weight of homozygotes lag behind non-Tg and hemizygous littermates. The Jackson Lab: Stock# 012836; Cryopreserved. The CRO Scantox Neuro offers research services with this model. Wils et al., 2010 Yes
<p>-</p>, <p>Wild-type TDP-43 transgenic (line 3C)</p>, <p>TDP-43<sub>PrP</sub></p> C57BL/6-Tg(Prnp-TARDBP)3cPtrc/J Transgene injected into fertilized C57BL/6 oocytes. Founders bred with B6. TARDBP Transgene expresses wild-type human TARDBP driven by the mouse prion protein (Prp) promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia No overt neuronal death, but degenerating neurites and axons, gliosis, and vacuolization of myelin. Abnormal aggregates of mitochondria present as eosinophilic aggregates in spinal motor neurons. Dendritic spine loss in the hippocampus. Homozygous mice develop body tremors and gait impairments leading to a “swimming gait” and severe motor deficits requiring euthanasia. Early reductions in body and brain weight in homozygous mice. Reduced dendritic spines in the hippocampus and lower mRNA levels of synaptic markers. The Jackson Lab: Stock# 016608; Cryopreserved Xu et al., 2010 Yes
<p>-</p>, <p>WT-TAR6/6</p>, <p>TAR6/6</p> Transgene introduced into BL6/SJL oocytes. Founders crossed to C57BL6/J. TARDBP Transgene encodes wild-type human TARDBP, driven by the murine Thy-1.2 promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Accumulation of transgenic and C-terminal fragments of TDP-43 in the cytoplasm, upper and lower motor neuron loss, astrogliosis, and microgliosis. Motor impairments as early as 6 weeks, reduced anxiety and disturbed nest-building behavior. Early death—average survival is 6.7 months. The CRO Scantox Neuro offers research with TAR6/6 mice. Wils et al., 2010, Scherz et al., 2018 Yes
<p>line 102</p> B6.Cg-Tg(tetO-APPSwInd)102Dbo/Mmjax C57BL/6 x C3HeJ; backcrossed to C57BL/6 APP APP K670_M671delinsNL (Swedish), APP V717F (Indiana) Mouse APP695 with a humanized Aβ region and the Swedish (KM570/571NL) and Indiana (V617F) mutations downstream of a tetracycline-responsive promoter and mouse prion protein exons 1-2. APP: Transgenic Alzheimer's Disease APP protein 10-30x higher than endogenous mouse APP. Progressive amyloid plaques starting at 2 months. Extensive amyloid pathology by 9 months especially in the cortex and hippocampus. Amyloid pathology is halted by transgene suppression but existing plaques are stable. Highest doxycycline sensitivity relative to lines 107 and 885. Hyperactivity. The Jackson Lab; available through the JAX MMRRC Stock# 034845; Cryopreserved Jankowsky et al., 2005 No
<p>line 107</p> B6.Cg-Tg(tetO-APPSwInd)107Dbo/Mmjax C57BL/6 x C3HeJ; backcrossed to C57BL/6 APP APP K670_M671delinsNL (Swedish), APP V717F (Indiana) Mouse APP695 with a humanized Aβ region and the Swedish (KM570/571NL) and Indiana (V617F) mutations downstream of a tetracycline-responsive promoter and mouse prion protein exons 1-2. APP: Transgenic Alzheimer's Disease APP protein 10-30x higher than endogenous mouse APP. Progressive amyloid plaques starting at 2 months. Extensive amyloid pathology by 9 months especially in the cortex and hippocampus. Amyloid pathology is halted by transgene suppression but existing plaques are stable. Intermediate expression of transgene and doxycycline sensitivity relative to lines 102 and 885. Hyperactivity. The Jackson Lab; available through the JAX MMRRC Stock# 034846; Cryopreserved Jankowsky et al., 2005 No
<p>line 885</p> B6C3-Tg(tetO-APPSwInd)885Dbo/Mmjax C57BL/6 x C3HeJ; backcrossed to C57BL/6 APP APP K670_M671delinsNL (Swedish), APP V717F (Indiana) Mouse APP695 with a humanized Aβ region and the Swedish (KM570/571NL) and Indiana (V617F) mutations downstream of a tetracycline-responsive promoter and mouse prion protein exons 1-2. APP: Transgenic Alzheimer's Disease APP protein 10-30x higher than endogenous mouse APP. Progressive amyloid plaques starting at 2 months. Extensive amyloid pathology by 9 months especially in the cortex and hippocampus. Amyloid pathology is halted by transgene suppression but existing plaques are stable. Highest transgene expression and highest doxycycline requirement relative to lines 102 and 107. Hyperactivity. The Jackson Lab; available through the JAX MMRRC Stock# 034834; Cryopreserved Jankowsky et al., 2005 No
<p>-</p>, <p>Hsiao mice</p>, <p>App-Swe</p>, <p>App-sw</p>, <p>APP(sw)</p>, <p>APPSwe</p> B6;SJL-Tg(APPSWE)2576Kha B6;SJL Mixed Background APP APP K670_M671delinsNL (Swedish) The human APP gene (isoform 695) containing the double mutation K670N, M671L (Swedish mutation) under the control of the hamster prion protein. APP: Transgenic Alzheimer's Disease Numerous parenchymal Aβ plaques by 11-13 months with some vascular amyloid. Oxidative lipid damage, astrogliosis and microgliosis. No tangles or neuronal loss. Impaired spatial learning, working memory, and contextual fear conditioning reported at <6 months although other studies have reported normal cognition at this age with progressive impairment by >12 months. Between 7 -12 weeks males become aggressive and begin to fight. Premature mortality: mortality of >20% anticipated, particularly in males. Taconic: Stock #1349. Charles River, PsychoGenics, and Scantox Neuro offer research services with this line. Hsiao et al., 1996 Yes
<p>APPSwe-Tau</p>, <p>APPSwe(2576)/TauJNPL3</p>, <p>TAPP</p> Tg(APPSWE)2576Kha; Tg(Prnp-MAPT*P301L)JNPL3Hlmc C57BL/6, DBA/2, SJL, SW Mixed Background APP, MAPT APP K670_M671delinsNL (Swedish), MAPT P301L Generated by crossing Tg2576 mice, which have the transgene for human APP (isoform 695) carrying the Swedish mutation with mice expressing human MAPT (4 repeat) with the P301L mutation. APP; MAPT: Transgenic Alzheimer's Disease Gradual appearance of plaques; by 9 months plaques are scattered throughout the cortex, hippocampus, and amygdala similar to Tg2576. Tau pathology more extensive than JNPL3. Astrocytosis and microgliosis. Motor disturbances similar to JNPL3, with identical range in age of onset. Reduced vocalization and decreased grooming. Progressive hindlimb weakness. Hunched posture. Eye irritations. Some mice have the Pde6brd1 retinal degeneration mutation which can cause light sensitivity and/or blindness and may affect behavioral testing. Taconic: Stock# 2469 Lewis et al., 2001 Yes
<p>-</p>, <p>Tg-Aβ(4-42)</p> C57BL6 APP Transgenic encodes N-truncated human Aβ (Aβ4-42) fused to the murine thyrotropin releasing hormone signal peptide under the control of the Thy1 promoter. APP: Transgenic Alzheimer's Disease Aβ4-42 is dectable starting at two months, predominantly in the CA1 region of the hippocampus, but also in the occipital cortex, piriform cortex, striatum, and superior colliculus. Age- and dose-dependent hippocampal neuronal loss is seen in the CA1 region as well as microgliosis and astrogliosis. Age-dependent spatial learning deficit as demonstrated in the Morris water maze, specifically, the absence of a preference for the target quadrant starting at eight months in homozygous mice and at 12 months in hemizygous mice. Impaired contextual fear conditioning. Intact vision and motor abilities. Available through Thomas Bayer. Bouter et al., 2013 Yes
B6CBA-Tg(Thy1.2-hAPParc) C57BL/6-CBA APP APP E693G (Arctic) Transgenic mice with human APP (isoform 695) bearing the Arctic APP mutation (E693G). APP: Transgenic Alzheimer's Disease Mild amyloid pathology with a relatively late onset, starting with intracellular Aβ, then diffuse extracellular Aβ deposits in the subiculum, expanding to interconnected brain regions such as retrosplenial granular cortex, thalamus, and mammillary bodies. Pathology more severe in females. Spatial learning and memory deficit in the Barnes maze test in heterozygous females mice at 15 months. Available through Annica Rönnbäck Rönnbäck et al., 2011 No
<p>-</p>, <p>Tg-Swe</p> C57BL/6J APP APP K670_M671delinsNL (Swedish) Transgene with human APP (isoform 695) bearing the Swedish mutation under the murine Thy1 promoter. APP: Transgenic Alzheimer's Disease Extracellular amyloid deposition begins at ~12 months. Intraneuronal Aβ aggregates at ~6 months. Extracellular pathology, both cerebrovascular amyloid angiopathy (CAA) and congophilic parenchymal plaques, mainly found in the cerebral cortex, hippocampus and thalamus. Aβ-burden in cerebral cortex is approximately 1.0% (at 12 months) and 2.8% (at 18 months). Unknown. Available through Lars Nilsson Philipson et al., 2009, Lord et al., 2006 Yes
R1 line of ES cells APP APP K670_M671delinsNL (Swedish) Modification of mouse APP sequence to introduce the Swedish mutation and "humanize" the murine Aβ sequence by altering three amino acids. APP: Knock-In Alzheimer's Disease Accumulation of human Aβ. Unknown. Unknown Reaume et al., 1996 No
<p>-</p>, <p>tg ArcSwe</p>, <p>APP-ArcSwe</p> C57BL/6J APP APP K670_M671delinsNL (Swedish), APP E693G (Arctic) Transgene with human APP (isoform 695) containing both the Arctic (E693G) and Swedish (KM670/671NL) mutations under the murine Thy1 promoter. APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy Strong intraneuronal Aβ aggregation starting at 1 month and increasing with age. Extracellular amyloid plaque at 5-6 months, most consistent in the cerebral cortex, hippocampus, and thalamus. Congophilic parenchymal plaques are predominant, but some mice show marked CAA, particularly in the thalamus. Mild spatial learning deficits at 4-8 months in Morris water maze and impaired functioning in a passive avoidance test at 16 months. Tg-ArcSwe have reduced body weight compared with nontransgenic littermates. Available through Stina Syvänen or Lars Nilsson. Lord et al., 2006 Yes
<p>-</p>, <p>APP(swe/ind) CRND8</p> Hybrid C3H/He-C57BL/6 APP APP K670_M671delinsNL (Swedish), APP V717F (Indiana) Transgene contains human APP695 with the Swedish mutation (KM670/671/NL) and Indiana mutation (V717F) under the control of the hamster prion (PrP) gene promoter. The expression cassette includes about 90 nucleotides of the APP 5'-untranslated region adjacent to the start codon and 269 nucleotides of the 3′-untranslated region. APP: Transgenic Alzheimer's Disease Rapid, early plaque development, with thioflavin S-positive amyloid deposits at 3 months; dense cored plaques and neuritic pathology by 5 months. Plaques become more extensive with age. More Aβ42 than Aβ40. Activated microglia appear concurrently with plaques, whereas GFAP+ astrocytes follow later, about 13-14 weeks. Dystrophic neurites at 5 months . Early impairment in acquisition and learning reversal in the reference memory version of the Morris water maze by 3 months. Cognitive deficits in the step-down inhibitory avoidance test at 7 months but not at 2 months. Similar to wild-type in motility, exploratory activity, or neuromuscular function at 7 months as evaluated by the rotarod, hole board and grip strength tests. Cholinergic dysfunction: decrease in the number of cholinergic neurons in the nucleus basalis magnocellularis by 7 months as measured by ChAT immunoreactivity. Enhanced auditory startle response and modest reduction in prepulse inhibition. Available through the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto Chishti et al., 2001 Yes
C57BL/6N APP APP K670_M671delinsNL (Swedish), APP S679C These transgenic mice express human APP (isoform 751) containing the Swedish (KM670/671NL) mutation and a serine-to-cysteine substitution at amino acid 679 (amino acid 8 within the Aβ sequence), under the control of the murine Thy1 promoter. APP: Transgenic Alzheimer's Disease, MCI due to AD Intracellular Aβ immunoreactivity in the hippocampus and cortex, beginning by 12 months. No amyloid plaques, hyperphosphorylated tau, microgliosis, astrogliosis, or neuron loss through 24 months. Learning deficits, as well as indicators of increased anxiety and depression, by 7 months. More rapid decay of hippocampal long-term potentiation, compared with wild-type mice. Age-dependent cholinergic loss in hippocampus; lower rates of serotonin turnover in hippocampus, ventral striatum, and amygdala. Available through Carsten Korth. Müller-Schiffmann et al., 2016 Yes
BRI2(Tg-FDD) Hybrid C3HeB/FeJ embryo; crossed to C57BL/6J ITM2B (BRI2) BRI2: Familial Danish Dementia (FDD) duplication The transgene, driven by the mouse prion promoter (Prnp), consists of the 795 form of human BRI(2) with a 10-nucleotide duplication-insertion (TTTAATTTGT). ITM2B (BRI2): Transgenic Familial Danish Dementia, Cerebral Amyloid Angiopathy, Alzheimer's Disease Widespread cerebral amyloid angiopathy (CAA) starting around 7 months. Deposition of the Danish amyloid subunit (ADan) in brain parenchyma and vessels, along with amyloid-associated gliosis and inflammation, intracellular and extracellular deposition of oligomeric ADan, and tau-positive deposits in neuropil, but no neurofibrillary tangles. Age-dependent abnormal grooming behavior. Around one year mice develop an arched back and walk with a wide-based gait and short steps. Feet clasping upon suspension of the mice by their tails. Available through Ruben Vidal Vidal et al., 2009 No
mAPP/DN-RAGE, APP/DN-RAGE C57BL/6 APP, RAGE (AGER) APP K670_M671delinsNL (Swedish), APP V717F (Indiana) Mice expressing a form of transgenic RAGE comprising a truncated form of the receptor with intact extracellular and membrane-spanning portions, but a deleted cytosolic tail driven by the PDGF-β promoter were crossed with mice expressing human APP carrying the Swedish and Indiana mutations driven by PDGF-β promoter (The Jackson Lab: Stock# 004661--now extinct). APP: Transgenic; RAGE (AGER): Transgenic Alzheimer's Disease Diminished neuropathology compared with mice expressing mutant APP alone at both 3–4 and 14–18 months of age. Preservation of spatial learning and memory compared with Tg-mAPP/RAGE animals. No abnormalities with respect to reproductive fitness, development, basic neurological functioning, or longevity. Available through Shirley ShiDu Yan Arancio et al., 2004 No
APP/RAGE C57BL/6 APP, RAGE (AGER) APP K670_M671delinsNL (Swedish), APP V717F (Indiana) Mice expressing human wild-type RAGE driven by the PDGF-β promoter were crossed with mice expressing human APP carrying the Swedish and Indiana mutations driven by PDGF-β promoter (The Jackson Lab: Stock# 004661-now extinct) APP: Transgenic; RAGE (AGER): Transgenic Alzheimer's Disease Increased activation of microglia and astrocytes compared to mice expressing mutant APP alone. Abnormalities in spatial learning and memory at 3-4 months of age, whereas deficits occur later in mice expressing mutant APP alone and are less severe. Available through Shirley ShiDu Yan Arancio et al., 2004 No
<p>APP-Swedish,Dutch,Iowa</p>, <p>APPSwDI</p> C57BL/6-Tg(Thy1-APPSwDutIowa)BWevn/Mmjax C57BL/6 APP APP K670_M671delinsNL (Swedish), APP E693Q (Dutch), APP D694N (Iowa) Transgenic mice with 2.1 kb of the human APP gene (isoform 770) with the Swedish (K670N/M671L), Dutch (E693Q) and Iowa (D694N) mutations under the control of the mouse Thy1 promoter. APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type Hemizygotes progressively accumulate insoluble Aβ40 and Aβ42, especially within brain microvessels starting at 3 months. Fibrillar Aβ in micovessels around 6 months. Diffuse plaque-like deposits around 3 months in the subiculum, hippocampus and cortex. Aβ deposits throughout the forebrain by 12 months. Impaired learning and memory in the Barnes maze task at 3, 9, and 12 months. Beginning at 3 months transgenic mice took longer to find the escape hole. No difference in mobility, strength or coordination. The Jackson Lab; available through the JAX MMRRC Stock# 034843; Live Davis et al., 2004 Yes
<p>-</p>, <p>mThy1-α-synuclein</p>, <p>mThy-1 tg</p>, <p>Tg(Thy1-SNCA)61Ema</p> B6;DBA-Tg(Thy1-SNCA)61Ema (C57BL/6 x DBA/2)F1 (strain of origin) SNCA This transgenic mouse expresses human wild-type α-synuclein under the control of the mouse Thy1 promoter (Rockenstein et al., 2002). The transgene is inserted in the X chromosome. SNCA: Transgenic Parkinson's Disease Available through Eliezer Masliah, Robert Rissman for academic research; others please contact the Office of Innovation and Commercialization at the University of California, San Diego. The CRO Scantox Neuro offers research services with this model. Rockenstein et al., 2002 Yes
<p>-</p>, <p>Tau22</p> C57BL6/CBA; backcrossed to C57BL6 MAPT MAPT G272V, MAPT P301S Transgene containing the cDNA of the 412 amino acid isoform of human 4-repeat tau mutated at sites G272V and P301S under a Thy1.2 promotor. MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease A variety of tau pathologies starting at 3 months, including neurofibrillary tangle-like inclusions, rare ghost tangles, and paired helical filament-like structures. Hyperphosphorylation of tau on many epitopes (e.g. AT8, AT100, AT180, AT270, 12E8, tau-pSer396, and AP422) and mild astrogliosis. Increased anxiety and delayed learning from 3 months, and reduced spatial memory at 10 months. No changes in overall motor activity and no gross motor deficits. Increased depression-like and aggressive behavior, co-occurring with disturbances in nocturnal activity. Fertile with normal frequency and size of litters. Stably transmits the transgene to offspring. Deficits in hippocampal synaptic transmission. Available through Luc Buée Schindowski et al., 2006 Yes
<p>Thy-1 mutated human tau</p>, <p>TAU 441</p>, <p>hTAU441</p>, <p>TAU441 V337M R406W</p> C57Bl/6xDBA MAPT MAPT V337M, MAPT R406W Transgene consists of human MAPT Tau441 (2N/4R) with mutations V337M and R406W under control of the Thy1 promoter. MAPT: Transgenic Alzheimer's Disease Increased total tau, and phosphorylated tau (Thr181, Ser199, Thr231) in amygdala and hippocampus starting at 3 months. Spatial memory deficits starting at 5 months (Morris water maze). Olfactory deficits at 5 months (Buried food test). No motor deficits (rota rod, beam walk) or depressive behavior (forced swim test). Olfactory deficits. The CRO Scantox Neuro offers research services with this line. Flunkert et al., 2013 Yes
Thy-1 PS1.M146V Transgene injected into fertilized oocytes from pure C57BL/6 mice. PSEN1 PSEN1 M146V Transgene encoding human PSEN1 carrying the M146V mutation. Transgene is driven by the murine Thy-1 promoter. PSEN1: Transgenic Alzheimer's Disease No plaques. Unknown. Unknown Howlett et al., 2004 No
<p>-</p>, <p>BAC-TREM2</p> FVB/NJ TREM2 The BAC (RP11-237K15) transgene contains the TREM2 coding region and surrounding genomic regions (>50 kb on each side) with conserved gene regulatory elements. Key coding exons were deleted from other TREM-like genes contained in the BAC, to prevent their expression. Transgenic mice were generated and maintained on the FVB/NJ background. TREM2: Transgenic Alzheimer's Disease No obvious neuropathology is observed at 4, 7 and 11 months of age. Normal contextual fear conditioning at 10 months of age. Normal LTP at 10 months of age. Available through X. William Yang. Lee et al., 2018 Yes
<p>-</p>, <p>BAC-TREM2 X&nbsp;5xFAD</p> TREM2-BAC: FVB/NJ; 5xFAD: C57BL/6 X SJL TREM2, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V TREM2-BAC mice were crossed with 5xFAD mice. TREM2: Transgenic; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques with plaque-associated microgliosis. Reduced plaque burden, altered microglial and plaque morphology, and less severe plaque-associated neuritic dystrophy, compared with 5xFAD. 5xFAD/TREM2 mice perform comparably to wild-type mice in a contextual fear conditioning test, while 5xFAD mice are impaired. TREM2-BAC: Available through X. William Yang. 5xFAD: The Jackson Lab; available through the JAX MMRRC Stock# 034840; Live Lee et al., 2018 Yes
B6(C3)-Trem2tm1c(EUCOMM)Wtsi/AdiujJ B6(C3) Trem2 Targeted insertion of LoxP sites flanking exons 2 and 3 of the mouse Trem2 gene. Trem2: Knock-In Alzheimer's Disease, Frontotemporal Dementia, Nasu-Hakola Disease No data. No data. The Jackson Lab: Stock# 029853; Live The Jackson Laboratory No
C57Bl/6J Trem2 TREM2 H157Y CRISPR/Cas9 gene editing was used to introduce the H157Y mutation into the mouse Trem2 gene. Trem2: Knock-In Alzheimer's Disease Microglial density and morphology did not differ between carriers of the H157Y variant and wild-type mice. Trem2-H157Y knock-in did not differ from wild-type mice at 6 months of age in tests of anxiety, associative memory, and spatial working memory. Enhanced hippocampal synaptic plasticity was observed in mice homozygous for the H157Y variant, compared with wild-type mice. Available through Na Zhao (zhao.na@mayo.edu). Qiao et al., 2023 Yes
C57Bl/6J Trem2, APP, PSEN1 TREM2 H157Y, APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V CRISPR/Cas9 gene editing was used to introduce the H157Y mutation into the mouse Trem2 gene. The resulting Trem2-H157Y knock-in mice were then intercrossed with 5xFAD mice. Trem2: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Age-dependent effects on amyloid-β pathology and gliosis. At 4 months, plaque burdens, microgliosis, and astrogliosis were similar among genotypes. By 8.5 months, amyloid burdens, microgliosis, and astrogliosis were reduced in homozygous carriers of the H157Y variant, compared with 5xFAD mice homozygous for wild-type Trem2. Unknown. Increased TREM2 shedding, decreased TREM2 signaling, and accelerated Aβ42 clearance from the interstitial fluid in 5xFAD homozygous for Trem2 H157Y, compared with 5xFAD homozygous for wild-type Trem2. Downregulation of disease-associated microglia (DAM) genes, microglial immune-related genes, genes encoding inflammatory cytokines, and genes expressed by astrocytes in H157Y homozygotes. Trem2-H157Y knock-in mice are available through Na Zhao (zhao.na@mayo.edu). 5xFAD mice are available from The Jackson Laboratory, JAX MMRRC Stock# 034848. Qiao et al., 2023 Yes
<p>-</p>, <p>CV<sup>+</sup>mTrem2<sup>−/−</sup></p>, <p>CV-KO</p>, <p>TREM2<sup>CV</sup></p> C57BL/6 ×CBA, backcrossed for at least four generations to C57BL/6. TREM2, Trem2 BAC transgenic mice carrying human TREM2 (common variant), TREML1, and TREML2 were backcrossed to Trem2 knockout mice to yield mice that express the common variant of human TREM2 in the absence of mouse Trem2. TREM2: Transgenic; Trem2: Knock-Out Alzheimer's Disease Unknown. Unknown. TREM2 mice are available through Marco Colonna. Song et al., 2018 Yes
<p>-</p>, <p>CV<sup>+</sup>mTrem2<sup>−/−</sup>5XFAD</p> C57BL/6 X CBA, back-crossed for at least 4 generations to C57BL/6 Trem2, TREM2, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V BAC transgenic mice carrying human TREM2 (common variant), TREML1, and TREML2 were back-crossed to Trem2 KO mice (Colonna) to yield mice that express the common variant of human TREM2 in the absence of mouse Trem2. These mice were then crossed with 5xFAD mice. Trem2: Knock-Out; TREM2: Transgenic; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques surrounded by activated microglia. No data. Neurodegeneration-associated microglial activation markers elevated, compared with 5XFAD lacking TREM2. TREM2 mice: available through Marco Colonna; 5XFAD: The Jackson Lab; available through the JAX MMRRC Stock# 034848; Live Song et al., 2018 Yes
<p>-</p>, <p>R47H<sup>+</sup>mTrem2<sup>−/−</sup></p>, <p>R47H-KO</p>, <p>TREM2<sup>R47H</sup></p> C57BL/6 × CBA, backcrossed for at least four generations to C57BL/6. TREM2, Trem2 TREM2 R47H BAC transgenic mice carrying human TREM2 (R47H variant), TREML1, and TREML2 were backcrossed to Trem2 knockout mice to yield mice that express the R47H variant of human TREM2 in the absence of mouse Trem2. TREM2: Transgenic; Trem2: Knock-Out Alzheimer's Disease Unknown. Unknown. TREM2 mice are available through Marco Colonna. Song et al., 2018 Yes
<p>-</p>, <p>R47H<sup>+</sup>mTrem2<sup>−/−</sup>5XFAD</p> C57BL/6 X CBA, back-crossed for at least 4 generations to C57BL/6 Trem2, TREM2, APP, PSEN1 TREM2 R47H, APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V BAC-transgenic mice carrying the human TREM2 (R47H variant), TREML1, and TREML2 were back-crossed to Trem2 KO mice (Colonna) to yield mice that express the R47H variant of human TREM2 in the absence of mouse Trem2. These mice were then crossed with 5XFAD mice. Trem2: Knock-Out; TREM2: Transgenic; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Lower density of activated microglia surrounding amyloid plaques in 5XFAD mice expressing the R47H variant of human TREM2 compared with those expressing the common variant. No data. TREM2 mice: available through Marco Colonna; 5XFAD: The Jackson Lab; available through the JAX MMRRC Stock# 034848; Live Song et al., 2018 Yes
<p>-</p>, <p>Trem2-IPD</p> B6-Trem2em2Npa C57BL/6J Trem2 CRISPR/Cas9 gene editing was used to disrupt the ADAM10/17 recognition site on TREM2, changing histidine-157 to isoleucine (I), serine-158 to proline (P), and threonine-159 to aspartate (D). Trem2: Knock-In Alzheimer's Disease At 3 months of age, TREM2-IPD mice had more Tmem119-positive microglia and a greater percentage of proliferating microglia than mice expressing wild-type Trem2. Unknown. Levels of soluble TREM2 were decreased and levels of cell-surface TREM2 were increased in TREM2-IPD mice, compared with wild-type. The IPD mutation accelerated microglial maturation and increased microglial phagocytic activity. Available from Novartis Pharma AG under an MTA. Contact Ivan Galimberti (ivan.galimberti@novartis.com) or Derya Shimshek (derya.shimshek@novartis.com). Dhandapani et al., 2022, Beckmann et al., 2023 Yes
<p>-</p>, <p>TREM2-IPDxAPP23xPS45</p>, <p>APP23xPS45xIPD</p> C57BL/6 Trem2, APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1 G384A Trem2-IPDxAPP23xPS45 mice have a modified murine Trem2 gene (resulting in disruption of the ADAM protease cleavage site after amino acid 157) and carry transgenes for human APP and PSEN1 with the AD-linked Swedish and G384A mutations, respectively. Trem2: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques, plaque-associated neuritic dystrophies, microgliosis. Pathology exacerbated in Trem2-IPDxAPP23xPS45 mice, compared with APP23xPS45 mice expressing wild-type Trem2, at an early—but not late—stage of plaque deposition. Unknown. Microglial maturation accelerated in Trem2-IPDxAPP23xPS45  mice, compared with APP23xPS45 mice expressing wild-type Trem2. TREM2-IPD and PS45 mice are available from Novartis Pharma AG under an MTA. Contact Ivan Galimberti (ivan.galimberti@novartis.com) or Derya Shimshek (derya.shimshek@novartis.com). APP23 mice are available through The Jackson Laboratory Stock# 030504, Live. Dhandapani et al., 2022 Yes
<p>-</p>, <p>Trem2<sup>-/-</sup> (Colonna)</p> C57BL/6 -TREM2tm1cln C57BL/6 Trem2 Inactivation of the mouse Trem2 gene by targeted deletion of exons 3 and 4 Trem2: Knock-Out Nasu-Hakola Disease, Frontotemporal Dementia, Alzheimer's Disease Microglial number remains constant and microglial size decreases with age in the corpus callosum of Trem2 KO mice, while microglial number increases and microglial size remains stable in wild-type mice. No cognitive/behaviorial deficits observed. Osteopenic. Impaired microglial response to experimental demyelination, middle cerebral artery occlusion, and facial nerve axotomy. Available through Marco Colonna Turnbull et al., 2006 Yes
<p>-</p>, <p>Trem2<sup>-/-</sup>5XFAD</p>, <p>mTrem2<sup>-/-</sup>5XFAD</p><p>&nbsp;</p> C57BL/6 -TREM2tm1cln; B6.Cg-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmja C57BL/6 Trem2, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V 5XFAD mice were crossed with Trem2 KO mice. TREM2 KO: Targeted deletion of exons 3 and 4 of mouse Trem2. 5XFAD express two transgenes: 1) human APP with the Swedish, Florida and London mutations, containing the 5' untranslated region and driven by the mouse Thy1 promoter and 2) human PSEN1 with the M146L and L286V mutations driven by the mouse Thy1 promoter. Trem2: Knock-Out; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Compared with 5XFAD, mice deficient in TREM2 show an age- dependent increase in amyloid accumulation in the hippocampus, more severe plaque-associated neuritic dystrophy, and exaggerated neuron loss in the cortex. Microglial containment of plaques is compromised in TREM2-deficient animals. Microglia accumulate autophagosomes. No data. Trem2 KO: available through Marco Colonna. 5XFAD: The Jackson Lab; available through the JAX MMRRC Stock# 034848; Live Wang et al., 2015 Yes
<p>-</p>, <p>Trem2<sup>-/-</sup>PS19</p> C57BL/6 -TREM2tm1cln; B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle/J C57BL/6 Trem2, MAPT MAPT P301S Trem2 KO (Colonna) mice were crossed with PS19 mice. TREM2 KO: Inactivation of the mouse Trem2 gene was achieved by targeted deletion of exons 3 and 4. PS19: express human MAPT (1N4R) with the P301S mutation, driven by the mouse prion protein (Prnp) promoter. Trem2: Knock-Out; MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease Microgliosis, astrogliosis, and brain atrophy in Trem2-/-PS19 mice are greatly attenuated compared with Trem2+/+PS19 animals. No data. Trem2 KO: available through Marco Colonna. PS19: The Jackson Lab: Stock# 008169; Live Leyns et al., 2017 Yes
C57BL/6J-Trem2em2Adiuj/J C57BL/6J Trem2 Trem2 expression was ablated using CRISPR/Cas9. Non-homologous end joining resulted in a 175-bp deletion that introduced a stop codon at amino acid 17. Trem2: Knock-Out Alzheimer's Disease, Frontotemporal Dementia, Nasu-Hakola Disease No data.. No data. The Jackson Lab: Stock# 027197; Live The Jackson Laboratory Yes
<p>-</p>, <p>Trem2 −/− (KOMP)</p> Trem2tm1(KOMP)Vlcg C57BL/6N Trem2 The entire coding region of the Trem2 gene was replaced by Velocigene cassette ZEN-Ub1 (lacZ -p(A)-loxP-hUbCpro-neor-p(A)-loxP). Trem2: Knock-Out Nasu-Hakola Disease, Frontotemporal Dementia, Alzheimer's Disease No data. At six months, mice perform normally in the open-field test, elevated plus maze, three-chamber social-interaction test, and contextual and cued fear-conditioning test. Trem2−/− microglia show a muted response to excitotoxicity in vivo, and decreased proliferation and increased apoptosis in vitro. Overexpression of Treml1 is driven by an ectopic Ubiquitin C promoter in the selection cassette. UC Davis KOMP Repository, Project VG10093, cryo-recovery or sperm Kang et al., 2018 Yes
<p>-</p>, <p>APPPS1;Trem2<sup>-/-</sup></p> TREM2tm1(KOMP)Vlcg; B6.Cg-Tg(Thy1-APPSw,Thy1-PSEN1*L166P)21Jckr C57BL/6 Trem2, APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1 L166P Trem2-/-: The entire coding region of the Trem2 gene was replaced by Velocigene cassette ZEN-Ub1 (lacZ-p(A)-loxP-hUbCpro-neor-p(A)-LoxP). APPPS1: Mice express human APP with the Swedish (K670M/N671L) mutations and human PSEN1 with the L166P mutation, both under control of the Thy1 promoter. Trem2: Knock-Out; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Reduced plaque burden at early stages of plaque deposition but increased plaque burden at later stages, fewer plaque-associated myeloid cells and astrocytes, less phospho-tau in plaque-associated dystrophic neurites, compared with APPPS1. No data. APPPS1 available through Mathias Jucker; Trem2 KO available through UC Davis KOMP Repository, Project VG10093, cryo-recovery or sperm Jay et al., 2015, Jay et al., 2017 Yes
<p>-</p>, <p>hTau;Trem2<sup>−/−</sup></p> TREM2tm1(KOMP)Vlcg; B6.Cg-Mapttm1(EGFP)Klt Tg(MAPT)8cPdav/J C57BL/6 Mapt, MAPT, Trem2 Htau mice were bred to Trem2−/− mice (Trem2tm1(KOMP)Vlcg) to generate hTau;Trem2−/− and htau/Trem2+/+ mice. These mice were backcrossed for four generations, and maintained on a C57BL/6 background. Mapt: Knock-Out; MAPT: Transgenic; Trem2: Knock-Out Nasu-Hakola Disease, Alzheimer's Disease, Frontotemporal Dementia Tau phosphorylation and aggregation in the cortex are enhanced in htau mice lacking TREM2, but reactive microglia are smaller and their processes have fewer branches. No data. Levels of stress-related protein kinases are elevated in the cortices and hippocampi of hTau;Trem2−/− compared with htau;Trem2+/+ mice. htau: The Jackson Lab: Stock# 005491, live; research services with this line available from the CRO Scantox Neuro. Trem2 KO: UC Davis KOMP Repository, Project VG10093, cryorecovery or sperm. Bemiller et al., 2017 Yes
<p>-</p>, <p>TREM2 Reporter Mouse</p> B6J-Trem2em4(mKate2)Bwef C57Bl/6J CRISPR/Cas9 gene editing was used to insert the reporter construct into the mouse Trem2 locus, immediately downstream of exon 5. This construct contained a P2A (peptide 2A) sequence followed by mKate2 with the KDEL endoplasmic reticulum-retention sequence fused to its C terminus. Silent mutations were also introduced into Trem2 to aid in genotyping. Alzheimer's Disease, Frontotemporal Dementia, Nasu-Hakola Disease Unknown. Unknown. Bicistronic expression of endogenous Trem2 and the fluorescent protein mKate2 under control of the endogenous Trem2 promoter. Available through Christian Haass. Feiten et al. No
<p>-</p>, <p>Trem2*R47H<sup>HSS</sup></p> B6.Cg-Trem2em4Adiuj/J C57BL/6J Trem2 TREM2 R47H CRISPR/Cas9 was used to edit the mouse Trem2 locus in the Trem2 R47H KI (JAX) model (JAX #27918), “humanizing” the cryptic splice acceptor site in exon 2 in the context of the existing R47H point mutation and two silent mutations. Trem2: Knock-In Alzheimer's Disease Unknown. Unknown. Register interest at The Jackson Laboratory, Stock No. 033781. The Jackson Laboratory Yes
<p>-</p>, <p>R47H ki</p> Trem2em2 Bwef C57BL/6N Trem2 TREM2 R47H CRISPR/Cas9 was used to introduce an R47H point mutation (arginine CGC > histidine CAC) and three silent mutations (glycine: GGG > GGT; arginine: AGA > CGA; lysine: AAG > AAA) into the mouse Trem2 gene. The silent mutations were added to aid in genotyping and increase the efficiency of gene editing. Trem2: Knock-In Alzheimer's Disease Unknown. Unknown. R47H KI mice exhibit a gene-dose-dependent reduction in expression of Trem2, due to aberrant splicing of the mutant allele. Available through Christian Haass. Xiang et al., 2018 Yes
<p>-</p>, <p>MODEL-AD R47H</p>, <p>Trem2*R47H<sup>CSS</sup> (for cryptic splice site)</p>, <p>B6.Trem2*R47H</p> C57BL/6J-Trem2em1Adiuj/J C57BL/6J Trem2 TREM2 R47H CRISPR/Cas9 was used to introduce an R47H missense mutation and two silent mutations—to aid in genotyping and increase gene-editing efficiency—into the mouse Trem2 gene. Trem2: Knock-In Alzheimer's Disease No neuron loss, amyloid plaques, or neurofibrillary tangles were observed in mice up to 24 months of age. Locomotor activity, motor coordination, and working memory similar to wild-type at 2 and 12 months of age. Compared with wild-type mice: age-, sex-, and region-dependent differences in glucose uptake and cerebral blood flow; increased mortality of females at 24 months of age; downregulation of genes related to immune function, and degradation of biological material in aged mice. The Jackson Lab:Stock# 027918; Cryorecovery. Kotredes et al., 2021, Tran et al., 2023 Yes
<p>-</p>, <p>Trem2<sup>+/R47H</sup></p> C57BL6/J Trem2 TREM2 R47H CRISPR/Cas9 was used to introduce the R47H variant into the endogenous mouse Trem2 gene. Trem2: Knock-In Alzheimer's Disease No 6E10- or Thioflavin S-positive amyloid plaques were observed at 4 months of age. Unknown. Approximate 40 percent decrease in levels of Trem2 mRNA in cortices of Trem2+/R47H mice compared with Trem2+/+ mice. Available through Gary Landreth or Bruce Lamb. Cheng-Hathaway et al., 2018 Yes
<p>-</p>, <p>APPPS1-21;Trem2<sup>+/R47H</sup></p> C57BL6/J Trem2, APP, PSEN1 TREM2 R47H, APP K670_M671delinsNL (Swedish), PSEN1 L166P To create Trem2+/R47H mice, CRISPR/Cas9 was used to introduce the R47H variant into the endogenous mouse Trem2 gene. APPPS1-21 mice express human APP with the Swedish (K670M/N671L) mutations and human PSEN1 with the L166P mutation, both under control of the Thy1 promoter. Trem2: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Reduction in the number and burden of fibrillar amyloid plaques in the hippocampus, fewer plaque-associated myeloid cells, and worse plaque-associated neuritic dystrophy, compared with APPPS1-21 mice homozygous for wild-type Trem2. Unknown. Levels of Trem2 transcripts were reduced in APPPS1-21;Trem2+/R47H compared with APPPS1-21;Trem2+/+ and were similar to those in APPPS1-21 mice haploinsufficient for Trem2. Trem2+/R47H available through Gary Landreth or Bruce Lamb; APPPS1-21 available through Mathias Jucker. Cheng-Hathaway et al., 2018 Yes
<p>LOAD1</p>, <p>APOE4/Trem2*R47H</p>, <p>APOE*4/Trem2*R47H</p>, <p>APOE4.Trem2*R47H</p> B6(SJL)-Apoetm1.1(APOE*4)Adiuj Trem2em1Adiuj/J C57BL/6J APOE, Trem2 TREM2 R47H, APOE C130R (ApoE4) This double-mutant line was generated by crossing APOE4 KI mice (Jackson Lab Stock# 027894), which carry a humanized APOE4 gene, to Trem2 R47H KI mice (Jackson Lab Stock # 027918), which have an R47H missense mutation knocked into the mouse Trem2 gene. APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease No neuron loss, amyloid plaques, neurofibrillary tangles, vascular leakage, myelin loss, or reactive microglia in mice up to 24 months of age. Age-related changes in locomotor activity, motor coordination, and working memory, but no genotype-dependent differences through 24 months of age, compared with wild-type mice. Age-, sex-, and region-dependent differences in glucose uptake and cerebral blood flow, compared with wild-type mice. Increased mortality at 24 months of age. Down-regulation of genes related to immune function and degradation of biological material in aged mice. The Jackson Lab:Stock# 028709; Live Kotredes et al., 2021 Yes
<p>-</p>, <p>Trem2*R47H<sup>NSS</sup></p> B6(SJL)-Trem2em1Aduci/J C57BL/6J Trem2 TREM2 R47H CRISPR/Cas9 was used to edit the mouse Trem2 gene, introducing the R47H point mutation and 10 silent mutations in exon 2. Trem2: Knock-In Alzheimer's Disease Changes in microglial morphology at 4 months but not 12 months, compared with wild-type. Unknown. Age-dependent synaptic deficits and age-dependent differences in gene expression, compared with wild-type mice. When crossed with 5xFAD mice, blunted inflammatory responses at 4 months, but exaggerated responses at 12 months. Available from The Jackson Laboratory, Stock No. 034036. Tran et al., 2023, The Jackson Laboratory Yes
B6-Trem2em3Npa C57BL/6J Trem2 CRISPR/Cas9 gene editing was used to introduce a stop codon after H157 of murine Trem2. Trem2: Knock-In None Unknown. Unknown. Mice homozygous for the nonsense mutation express very low levels of sTREM2 and Trem2 mRNA. Compared with Trem2-KO mice, TREM2-sol mice show prolonged microglial responses to injury, increased vulnerability of bone marrow-derived macrophages (BMDM) to growth factor deprivation, and preservation of endo-lysosomal function in BMDM. Available under MTA from Novartis Pharma AG. Contact Derya Shimshek (derya.shimshek@novartis.com). Beckmann et al., 2023 Yes
<p>-</p>, <p>Trem2 p.T66M</p> Trem2em1Bwef Mixed DBA/2J, FVB/ N, C57BL/6J Trem2 TREM2 T66M A CA>TG substitution was introduced into the murine Trem2 gene using CRISPR/Cas9 genome editing, resulting in a threonine-to-methionine substitution at amino acid 66.. Trem2: Knock-In Frontotemporal Dementia Age-related microglial activation seen in wild-type mice is absent in homozygotes. No data. Reduced cerebral blood flow and reduced cerebral glucose metabolism in homozygotes. Bone marrow-derived macrophages from heterozygous and homozygous Trem2 T66M mice show reduced proliferation, survival, and phagocytosis. Available through Christian Haass Kleinberger et al., 2017 Yes
C57BL/6J-Trem2em3Adiuj/J C57BL/6J Trem2 TREM2 Y38C CRISPR/Cas9 was used to introduce a point mutation into the endogenous mouse Trem2 gene, resulting in a tyrosine-to-cysteine amino acid substitution at amino acid 38 (Y38C). Trem2: Knock-In Frontotemporal Dementia No data. No data. The Jackson Lab: Stock# 029725; Cryopreserved Yes
<p>-</p>, <p>Segmentally trisomic Ts(17<sup>16</sup>)65Dn</p>, <p>Down syndrome-segmental trisomy 16</p> B6EiC3Sn a/A-Ts(1716)65Dn/J B6/C3H Cesium irradiation produced a reciprocal translocation of chromosomes 16 and 17, creating a freely segregating, supernumerary chromosome Mmu1716 (1716). Multi-transgene Down's Syndrome, Alzheimer's Disease Elevation of APP and soluble Aβ in the brain without Aβ plaque pathology. Changes to tau 3R/4R splicing, augmenting tau mRNA stability and tau phosphorylation. Basal forebrain neurodegeneration; loss of NE neurons in locus coeruleus; hippocampal abnormalities; cholinergic neuron loss; reduced number of proliferating cells. Neuroinflammation and oxidative stress markers. Spatial learning and memory deficits, developmental delay in sensorimotor milestones, locomotor hyperactivity, lack of behavioral inhibition, and stereotypic behavior. Delayed motor acquisition, impaired coordination,  reduced attention. Reduced birthweight, muscular trembling, male sterility, blindness, and an abnormal facial appearance. Altered skeletal, pulmonary, immune, and cardiac functions. Vocalization and swallowing abnormalities. Elevated blood levels of Aβ40 and Aβ42. Available from The Jackson Lab: Stock# 001924. Also available as a strain without blindness from The Jackson Lab Stock# 005252. Davisson et al., 1990, Reeves et al., 1995 Yes
<p>-</p> B6.Cg-Vps35tm1.1Mjff/J C57BL/6J Vps35 This constitutive KI mouse model expresses the g.85,263,520G>A missense mutation in exon 15 of Vps35, which leads to the mutated (D620N) protein (Cataldi et al., 2018). The model was generated to drive mutant protein expression at physiological levels and avoid the confounds of random insertion. This KI model was created and maintained in C57Bl/6J mice (The Jackson Laboratory). Vps35: Knock-In Parkinson's Disease Loss of TH+ neurons in SNpc and TH+ terminals in striatum at 13-16 mos. Widespread axonal degeneration at 13 mos. Increased somatic α-synuclein in SNpc; α-synuclein oligomers and aggregates in ventral midbrain at 15-16 mos. Increased somatodendritic tau/p-tau with age, but no neurofibrillary pathology. Increased GFAP in SNpc, but not striatum at 15-16 mos. No microgliosis up to 16 mos. No deficits in the buried pellet test, measuring olfactory function, from 6-14 months. Deficits in mood (anxiety/apathy) and/or cognition on elevated plus maze, starting at 3 months (unpublished). No defects in gastrointestinal function up to 14 months of age. Available through The Jackson Laboratory, Stock# 023409, Cryopreserved. Cataldi et al., 2018, Chen et al., 2019, Niu et al., 2021 Yes
WSB.Cg-Tg(APPswe,PSEN1dE9)85Dbo/How WSB/EiJ APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 Mice carry two transgenes, a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9, each controlled by the mouse prion protein promoter. Transgenic mice on a congenic C57BL/6J background were backcrossed with WSB/EiJ mice for at least six generations. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques, plaque-associated gliosis, cerebral amyloid angiopathy; possible neuron loss in cortex and hippocampal area CA1 in females. Transgenic mice are hyperactive. Working memory (spontaneous alternation in the Y-maze) is normal at 7 to 8 months, but short-term memory (tested in the Y-maze) is impaired in females (data from males is not available, as wild-type males are unable to perform this test). Available from The Jackson Laboratory, Stock #25970. Onos et al., 2019 Yes
Rat Models (25)
<p>-</p>, <p>AgenT</p> Wistar APP, PSEN1 APP K670_M671delinsNL (Swedish), APP V717I (London), PSEN1 M146L (A>C) Adeno-associated viral vectors separately encoding human APP with the Swedish and London mutations and human PSEN1 with the M146L mutation were injected bilaterally into the hippocampi of young adult (8-week-old) rats. APP: Virus; PSEN1: Virus Alzheimer's Disease Amyloid plaques and cerebral amyloid angiopathy observed 30 months post-injection. Anti-phospho-tau immunostaining suggests the presence of (pre)tangle-like structures. No astrogliosis seen up to 30 months post-injection. Compared with control rats at 8 months post-injection, AAV-AD spent less time in the target quadrant of the Morris water maze in probe tests administered 3 and 5 days after training and less time in the center of the open field. At 8 months post-injection, long-term potentiation was impaired in hippocampal slices obtained from AAV-AD rats, compared with controls, but the groups did not differ with regards to long-term depression. Viral vectors are available through AgenT SAS under collaboration or partnership agreements. Audrain et al., 2017 Yes
F344-Tg(APP)21Besey Fischer 344 APP APP K670_M671delinsNL (Swedish), APP V717F (Indiana) A lentiviral vector carrying a human APP695 transgene was injected into Fischer 344 zygotes. This transgene contains the Swedish and Indiana mutations and is driven by the ubiquitin-C promoter. APP: Transgenic Alzheimer's Disease No plaques to 30 months of age. Necrotic neurons in hippocampus and cortex by 19 months, in females; neuron loss not observed in cortices of 19-month males. Male rats show deficits in Morris water maze as early as 3 months of age. Females show deficits in Barnes maze at 14 months of age. Available from the Rat Resource & Research Center, Stock# 00636; cryorecovery, sperm Agca et al., 2008 Yes
<p>-</p>, <p>App<sup>h</sup></p>, <p>App<sup>h/h</sup></p> Long-Evans App Three point mutations were introduced into the rat App gene to humanize the Aβ sequence (G5R, F10Y, and R13H of Aβ). App: Knock-In Alzheimer's Disease No plaques, neurofibrillary tangles, or neuron loss observed at three months, the oldest age reported. Unknown. Available through Luciano D'Adamio. Tambini et al., 2019 Yes
<p>-</p>, <p>App<sup>hu/hu</sup></p> Long Evans App CRISPR/Cas9 was used to introduce the following mutations into the endogenous App gene: G676R (G5R), F681Y (F10Y), R684H (R13H), numbered according to the 770 amino-acid isoform of human APP (position within the Aβ sequence). App: Knock-In Alzheimer's Disease No plaques or tangles were observed up to two years of age. Unknown. Levels of CTFβ and Aβ are elevated in the brains of these knock-in rats, compared with wild-type animals. Available through Lutgarde Serneels. Serneels et al., 2020 Yes
<p>-</p>, <p>App<sup>hu/hu</sup>;Psen1M139T<sup>+/+</sup></p> Long Evans App, Psen1 PSEN1 M139T Crispr/Cas9 was used to humanize the Aβ sequence within the rat App gene and to introduce the M139T mutation into the rat Psen1 gene. App: Knock-In; Psen1: Knock-In Alzheimer's Disease No plaques or tangles were observed up to 2 years of age. Unknown. Elevated levels of CTFβ and Aβ compared with wild-type rats. Increased Aβ42/Aβ40 ratio relative to rats homozygous for humanized App, but without the Psen1 mutation. Available through Lutgarde Serneels. Serneels et al., 2020 Yes
<p>-</p>, <p>App<sup>p</sup></p> Long-Evans App APP A673T (Icelandic) Four point mutations were introduced into the rat App gene to humanize the Aβ sequence (G5R, F10Y, and R13H of Aβ) and to add the Icelandic mutation A673T (numbered as in the 770-amino-acid isoform of human APP). App: Knock-In Alzheimer's Disease Unknown. Unknown. Available through Luciano D'Adamio. Tambini et al., 2020 Yes
<p>-</p>, <p>App<sup>s</sup></p> Long-Evans App APP K670_M671delinsNL (Swedish) Five point mutations were introduced into the rat App gene to humanize the Aβ sequence (G5R, F10Y, and R13H of Aβ) and to add the AD-linked Swedish double mutation, KM670/671NL (numbered as in the 770-amino-acid isoform of human APP). App: Knock-In Alzheimer's Disease No plaques, neurofibrillary tangles, or neuron loss observed at 3 months, the oldest age reported. Unknown. Increased amplitude and decreased frequency of miniature excitatory postsynaptic currents; deficits in paired-pulse facilitation at excitatory synapses. Available through Luciano D'Adamio. Tambini et al., 2019, Tambini et al., 2020 Yes
<p>-</p>, <p>App<sup>NL-G-F</sup> rat</p>, <p>APP Swe-Arc-Ibe knock-in rat</p> Sprague Dawley App APP K670_M671delinsNL (Swedish), APP E693G (Arctic), APP I716F (Iberian) This rat line, created using CRISPR/Cas9 technology, carries a humanized Aβ sequence (G676R, F681Y, and R684H) and three AD-linked mutations (Swedish, KM670/671NL; Arctic, E693G; and Iberian, I716F) in the endogenous rat App gene. App: Knock-In Alzheimer's Disease Amyloid plaques apparent as early as 1 month in homozygous knock-ins. No neurofibrillary tangles through 22 months of age, but increases in tau phosphorylation, aggregation, and conformational changes. Astrogliosis, microgliosis, synapse and neuron loss. Deficits in the Morris Water Maze task and a paired associate learning task as early as 5 and 7 months of age, respectively. Available through Bai Lu. Pang et al., 2022 Yes
Fischer 344 APP, PSEN1 APP K670_M671delinsNL (Swedish), APP V717F (Indiana), PSEN1 L166P APP+PS1 transgenic rats express human APP with the Swedish and Indiana mutations and human PSEN1 with the L166P mutation. Both transgenes are driven by the ubiquitin-C promoter. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques, cerebral amyloid angiopathy, and necrotic neurons in hippocampus and cortex by 19 months of age. Deficits in Barnes maze by 10 months of age. Unknown. Agca et al., 2016, Klakotskaia et al., 2018 Yes
<p>-</p>, <p>DJ-1 knockout rat</p> LE-Park7em1sage; HsdSage:LE-Park7em1Sage; formerly LEH-Park7tm1sage Long Evans Hooded Park7 (DJ1) Disruption of the DJ-1 gene by zinc finger nuclease (ZFN) technology. ZFNs were engineered to bind to a recognition sequence in exon 5 of PARK7 and cleave DNA. Park7 (DJ1): Knock-Out Parkinson's Disease Age-related decrease in dopaminergic neurons in the substantia nigra and locus coeruleus; approximately 50 percent reduction by 8 months. Striatal dopamine and serotonin levels elevated 2-3fold over wild-type levels. No change was found in TH-immunoreactivity in the ventral tegmental area or striatum. Enhanced olfactory detection, abnormal short-term memory, impaired coping behavior, reduced anxiety on light-dark box. Abnormalities in gait, paw positioning, strength, vocalizations, and tongue movements. In males, impaired licking, longer and more frequent ultrasonic vocalizations, and accelerated decrease in average call intensity with age. No increase in mortality up to 8 months of age. Available through Inotiv. Cryopreserved. (Previously available through Horizon Discovery (formerly Sage Labs), Cat #TGRL4830) Dave et al., 2014 Yes
<p>-</p>, <p>Line 10681</p>, <p>hBAC G2019S-LRRK2</p>, <p>LRRK2 G2019S rat</p> NTac:SD-Tg(LRRK2*G2019S)571CJLi Sprague-Dawley LRRK2 LRRK2 G2019S BAC construct carrying the human gene Lrrk2 with the G2019S mutation. LRRK2: Transgenic Parkinson's Disease No overt neurodegeneration out to 12 months of age. Elongated dopaminergic neurons. Elevated oxidative and nitrosative stress. No evidence of gliosis. No α-synuclein inclusions until challenged with exogenous α-synuclein. No change in dopamine levels. Mild abnormalities in motor behavior. Slightly more postural instability at 8 months of age (but not at 4 and 12 months). Slightly more rearing events at 12 months, but not at younger ages. Bone marrow myeloid progenitor numbers were decreased, but suppressive myeloid cells were increased at 6 to 11 months of age. Available through Taconic, Cat# 10681, Cryopreserved. Research services with this model are available from Scantox Neuro. West et al., 2014 Yes
<p>-</p>, <p>Lrrk2 knockout rat</p> LEH-Lrrk2tm1sage, HsdSage: LE-Lrrktm1sage, formerly known as TGRL4620 Long Evans Hooded Lrrk2 Zinc finger nuclease (ZFN) technology was used to generate a deletion of 10 base pairs in exon 30 of the rat Lrrk2 gene. This resulted in a frameshift and a premature stop codon in the same exon. Lrrk2: Knock-Out Parkinson's Disease Not observed. Protection against dopaminergic cell loss under conditions involving LPS or α-synuclein overexpression in the substantia nigra. No changes in basal or evoked release of dopamine. One assessment of Rotarod performance revealed no impairment at 12 months of age compared with wild-type rats. Abnormalities in peripheral organs, including the kidney, liver, and lung. Lifespan and organ function are not adversely affected by Lrrk2 knockout. Available through Inotiv, Live and cryopreserved. Baptista et al., 2013, Ness et al., 2013 Yes
<p>Cy23</p> Sprague-Dawley Mapt These tau knockout rats were created through transcription activator-like effector nuclease (TALEN)-mediated targeting of exon 2 of the rat Mapt gene. Mapt: Knock-Out Alzheimer's Disease None reported. Unknown. No gross phenotypes reported. Contact David Westaway, Institute for Neurodegenerative Diseases, UCSF. Ayers et al., 2024 No
HsdBrl:WH Wistar APP APP K670_M671delinsNL (Swedish), APP V717F (Indiana) Transgene contains entire coding region of human APP751 with the Swedish and Indiana mutations and approximately 900 bp of 3' non-translated sequence, driven by the murine Thy1.2 promoter. APP: Transgenic Alzheimer's Disease Hemizygotes: intraneuronal Aβ in hippocampus and cortex by one week, but no plaques even at advanced ages. Homozygotes: intraneuronal Aβ in hippocampus and cortex by one week; amyloid plaques in hippocampus beginning at 6 months, in cortex beginning at 13 months. Cognitive deficits are apparent by three months of age in both hemizygous and homozygous transgenic rats. Resting-state fMRI showed disrupted cingulate network connectivity by 9 to11 months; FDG-PET showed hypometabolism by 16 to 19 months (homozygotes). Breeding pairs available via a royalty agreement with McGill University; contact Adriana Ducatenzeiler. Leon et al., 2010 Yes
<p>-</p>, <p>Park2 KO</p>, <p>Parkin knockout rat</p> HsdSage:LE-Park2em1Sage; formerly LEH-Park2TM1sage Long Evans Hooded Park2 The rat Park2 gene was disrupted using zinc finger nuclease (ZFN) technology, in which targeted ZFN RNA was injected into fertilized eggs. The ZFNs were engineered to bind to a recognition site sequence in exon 4 of Park2 and cleave the DNA. When the resulting double strand break was repaired by non-homologous end joining, a deletion of five base pairs was created in the founder rat. This deletion led to a frame shift and the creation of a premature stop codon. Park2: Knock-Out Parkinson's Disease No significant changes in dopaminergic neurons in the substantia nigra nor striatal dopamine levels, but alterations in dopaminergic signaling were detected at an early age, as were disruptions in mitochondrial protein expression in striatum. No increase in α-synuclein. Evoked release of striatal glycine greater at 12 months versus wild-type rats. No behavioral deficits detected at 4, 6, and 8 months of age. However, at 2 months, male KO rats made fewer small stereotypic movements, such as scratching and grooming, than wild-type controls. At 2 months, male KO rats had a greater preference for methamphetamine than wild-type rats. Available through Inotiv. Cryopreserved as heterozygous embryos. (Previously available through Envigo). Dave et al., 2014 Yes
<p>-</p>, <p>Pink1 knockout rat</p>, <p>Park6 KO rat</p> HsdSage:LE-Pink1em1Sage; formerly LEH-Pink1tm1Sage-/- Long Evans Hooded Pink1 The rat Pink1 gene was disrupted using zinc finger nuclease (ZFN) technology. The ZFNs were engineered to bind to a recognition site in exon 4 of Pink1 and cleave the DNA. When the resulting double strand break was repaired, a deletion of 26 base pairs was created. This deletion lead to a frameshift and the creation of a premature stop codon. Pink1: Knock-Out Parkinson's Disease Age-related decrease in dopaminergic neurons in the substantia nigra; greater than 50 percent reduction at eight months. Alterations in striatal dopamine and serotonin levels. Progressive increase in α-synuclein aggregates and reduced brain volume across numerous regions. Increased ventricular volume. Alterations in cortical and striatal mitochondria. Abnormalities in gait, coordination, and strength. As early as 5 weeks of age, KOs had increased foot slips on the tapered balance beam, at 7 weeks they showed hind limb fatigue, which progressed to hind limb dragging, and by 2 months they exhibited alterations in oromotor (lingual) behaviors. Heavier than wild-type rats at 4, 6, and 8 months of age. No increase in mortality. Early (3 months of age) gene expression changes in whole blood, indicative of inflammation-related changes. Gastrointestinal dysfunction appears within 6 months of age. Available through Inotiv. Live. (Previously available through Envigo (formerly Horizon Discovery and Sage Labs), Cat# TGRL4690)  Dave et al., 2014 Yes
<p>-</p>, <p>Psen1<sup>LF</sup></p> Long-Evans Psen1, App PSEN1 L435F Rats carry a mutation in the endogenous Psen1 gene that is homologous to the human L435F mutation, as well as a humanized Aβ sequence within the endogenous App gene. Psen1: Knock-In; App: Knock-In Alzheimer's Disease None observed in 15-day-old rats. Unknown. Levels of Aβ43 are elevated in the brains of homozygous and heterozygous Psen1 mutation carriers. Available through Luciano D’Adamio. Tambini and D'Adamio, 2020 Yes
SHR MAPT SHR24 rats express a gene encoding amino acids 151-274 and 306-391 of human tau, driven by the mouse Thy1 promoter (the numbering of amino acids corresponds to that of the 441-amino acid isoform of human tau, variously referred to as tau 40, Tau-F, or 2N4R). MAPT: Transgenic Alzheimer's Disease Neurofibrillary tangles accumulate in cortex, hippocampus, thalamus, and brainstem, beginning at 9 to 10 months. No neuron loss was observed in the hippocampus or cortex. SHR24 rats exhibit age-dependent impairments in several neurobehavioral tests; hind-limb clasping during the tail-hang test is one of the earliest abnormalities to appear, evident by 3.5 months of age. SHR24 rats have a shorter lifespan (approximately 14 months) than wild-type SHR rats (22-24 months). Unknown. Filipcik et al., 2012, Valachova et al., 2018 Yes
SHR MAPT SHR318 rats express a gene encoding amino acids 151-391 of human tau, driven by the mouse Thy1 promoter (the numbering of amino acids corresponds to that of the 441-amino acid isoform of human tau, variously referred to as tau 40, Tau-F, or 2N4R). MAPT: Transgenic Alzheimer's Disease Neurofibrillary tangles first appear at 9 months and are particularly prominent in the brainstem and spinal cord. Axonal degeneration is observed in the brainstem and spinal cord of 10- to 12-month animals. At 4.5 months, rats show normal learning, but deficits in spatial memory, in the Morris water maze. Reflexes and sensorimotor coordination are impaired at 7 months. SHR72 rats have a shorter lifespan (approximately 10–12 months) than wild-type SHR rats (22–24 months). No longer available. Zilka et al., 2006, Hrnkova et al., 2007 Yes
SHR MAPT SHR72 rats express a gene encoding amino acids 151-391 of human tau, driven by the mouse Thy1 promoter (the numbering of amino acids corresponds to that of the 441-amino acid isoform of human tau, variously referred to as tau 40, Tau-F, or 2N4R). MAPT: Transgenic Alzheimer's Disease Neurofibrillary tangles, demonstrated by Gallyas silver stain, were found the brainstems and spinal cords of terminal stage (7- to 8-month old) animals. Chromatolytic neurons and damaged axons were also observed at this stage. Sensorimotor deficits and loss of muscle strength are apparent at 3 months. This stage lasted about three months, and then rats experienced a rapid, dramatic decline in neurological function, succumbing within several days. SHR72 rats have a shorter lifespan (approximately 7-8 months) than wild-type SHR rats (22-24 months). Unknown. Koson et al., 2008 Yes
Spontaneously hypertensive stroke-prone (SHRSP); Fischer 344 APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 TgF344-AD rats, which carry human APP and PSEN1 transgenes, with the AD-linked Swedish and Δ exon 9 mutations, respectively, were backcrossed with spontaneously-hypertensive-stroke-prone (SHRSP) rats. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease, Vascular Dementia Amyloid plaques, microgliosis, and possible astrogliosis. Occasional neurons appear to contain paired helical filament tau. Demyelination. Reduced calbindin immunoreactivity and increased levels of caspase-cleaved actin may indicate neuron loss. Hyperactive. Working memory deficits as assessed by novel object recognition, but not as assessed by spontaneous alternation in the Y-maze. Hypertensive. Available through Sally Frautschy. Denver et al., 2019 Yes
<p>-</p>, <p>α-synuclein (E46K) rat, founder line 70</p>, <p>Human α-synuclein E46K rat</p>, <p>E46K aSyn Rat</p>, <p>Alpha-synuclein E46K Rat (BAC Tg)</p> NTac:SD-Tg(SNCA*E46K)70CJLi Sprague-Dawley SNCA SNCA E46K A bacterial artificial chromosome (BAC) was used to introduce human α-synuclein with the E46K mutation. SNCA: Transgenic Parkinson's Disease No overt neuronal loss. Accumulation of mutant α-synuclein in the brain, in the form of diffuse staining and intracellular aggregates. Aggregates were largely restricted to dopaminergic neurons of the substantia nigra and ventral tegmental area. Elevated nitrotyrosine in dopaminergic neurons. No overt behavioral changes until challenged with low-dose rotenone, upon which the rats exhibit bradykinesia, postural instability, and rigidity. Viable and fertile. Available through Taconic Cat #10679; Cryopreserved. Cannon et al., 2013 Yes
Sprague-Dawley MAPT MAPT P301S Tg12099 rats express the 0N4R isoform of human MAPT with P301S mutation linked to frontotemporal dementia, driven by the rat Prnp promoter. MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease Tau pathology, including neurofibrillary tangles, forebrain neurodegeneration, and astrogliosis in homozygotes. Hemizygotes exhibit little pathology, save for a few AT8-immunoreactive neurons in the entorhinal cortices of aged animals. Ataxia, bradykinesia, and seizures reported in aging homozygotes. Premature death of homozygotes, with median survival of 14 months. Contact David Westaway, Institute for Neurodegenerative Diseases, UCSF. Ayers et al., 2024 Yes
Fischer 344 APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 TgF344-AD rats express human APP with the Swedish mutation and human PSEN1 with the Δ exon 9 mutation. Both transgenes are driven by the mouse prion promoter. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques, microgliosis, and astrogliosis by 6 months. Neurofibrillary tangle-like structures at 16 months. Approximate 40 percent loss of neurons in hippocampus and cortex by 16 months. Earliest reported deficits are in reversal learning in the Morris water maze, apparent by 6 months. Available through Terrence Town. Cohen et al., 2013 Yes
<p>-</p>, <p>Trem2<sup>R47H</sup></p> Long-Evans Trem2, App TREM2 R47H Rats carry the R47H mutation in the endogenous Trem2 gene and a humanized Aβ sequence within the endogenous App gene. Trem2: Knock-In; App: Knock-In Alzheimer's Disease Unknown. Unknown. Available through Luciano D'Adamio. Tambini and D'Adamio, 2020 Yes

263 Visualizations

AD-related Research Models

Phenotypes Examined

  • Plaques
  • Tangles
  • Neuronal Loss
  • Gliosis
  • Synaptic Loss
  • Changes in LTP/LTD
  • Cognitive Impairment

When visualized, these phenotypes will distributed over a 18 month timeline demarcated at the following intervals: 3mo, 6mo, 9mo, 1yr, 15mo, 18mo+.

3xTg

Observed
  1. X
    Plaques at 26

    Extracellular Aβ deposits by 6 months in the frontal cortex, predominantly layers 4 and 5 and progress with age (Oddo et al., 2003).

  2. X
    Tangles at 52

    By 12 months extensive tau immunoreactivity in CA1 neurons of the hippocampus, particularly pyramidal neurons, later in the cortex. No tau pathology at 6 months (Oddo et al., 2003).

  3. X
    Gliosis at 30

    Increased density of GFAP immunoreactive astrocytes and IBA-1 immunoreactive microglia compared with wild-type mice at 7 months (Caruso et al., 2013). Development of gliosis may occur earlier.

  4. X
    Changes in LTP/LTD at 26

    By 6 months decreased LTP compared with wild type controls. Impairment in basal synaptic transmission. No change at 1 month of age (Oddo et al., 2003).

  5. X
    Cognitive Impairment at 17

    Cognitive impairment manifests at 4 months as a deficit in long-term retention and correlates with the accumulation of intraneuronal Aβ in the hippocampus and amygdala, but plaques and tangles are not yet apparent (Billings et al., 2005).

Absent
No Data
  • Neuronal Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Psen1, APP, MAPT APP K670_M671delinsNL (Swedish), MAPT P301L, PSEN1 M146V Psen1: Knock-In; APP: Transgenic; MAPT: Transgenic Alzheimer's Disease

Age-related, progressive neuropathology including plaques and tangles. Extracellular Aβ deposits by 6 months in frontal cortex, more extensive by 12 months. No tau pathology at 6 months, but evident at 12 months. Synaptic dysfunction, including LTP deficits, prior to plaques and tangles.

Cognitive impairment by 4 months. Impairments first manifest as a retention/retrieval deficit and not as a learning deficit, and occur prior to plaques and tangles. Deficits in both spatial and contextual based paradigms. Clearance of intraneuronal Aβ by immunotherapy rescues the early cognitive deficits in a hippocampal-dependent task.

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5xFAD (B6SJL)

Observed
  1. X
    Plaques at 8

    Extracellular amyloid deposition begins around 2 months, first in the subiculum and layer V of the cortex. Aβ42 also accumulates intraneuronally in an aggregated form within the soma and neurites starting at 1.5 months.

  2. X
    Neuronal Loss at 24

    Neuron loss in cortical layer V and subiculum.

  3. X
    Gliosis at 8

    Gliosis begins at 2 months.

  4. X
    Synaptic Loss at 16

    Levels of the presynaptic marker synaptophysin begin to decline by 4 months; levels of syntaxin, another presynaptic marker, and PSD-95, a postsynaptic marker, decline by 9 months

  5. X
    Changes in LTP/LTD at 24

    Basal synaptic transmission and LTP in hippocampal area CA1 begin to deteriorate between 4 and 6 months

  6. X
    Cognitive Impairment at 18

    Impaired spatial working memory in the Y-maze test and impaired remote memory stabilization in a contextual-fear-conditioning test by 4 to 5 months of age.

Absent
  • Tangles at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid pathology starting at 2 months, including amyloid plaques. Accumulation of intraneuronal Aβ before amyloid deposition. Gliosis and synapse degeneration. Neuron loss in cortical layer 5 and subiculum. No neurofibrillary tangles.

Age-dependent memory deficits including spatial memory, stress-related memory, and memory stablization. Motor phenotype.

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5xFAD (C57BL6)

Observed
  1. X
    Plaques at 8

    Amyloid plaques observed in hippocampus, cortex, thalamus, and spinal cord.

  2. X
    Neuronal Loss at 52

    Approximate 40 percent loss of layer V pyramidal neurons at one year.

  3. X
    Gliosis at 8

    Microgliosis and astrogliosis are associated with amyloid plaques; microgliosis is associated with vascular damage.

  4. X
    Synaptic Loss at 24

    Spine density was reduced in pyramidal neurons in somatosensory and prefrontal cortices, but not in the hippocampi, of 5xFAD mice crossed with mice expressing yellow fluorescent protein (YFP mice), compared with mice expressing YFP alone.

  5. X
    Changes in LTP/LTD at 8

    While spike-timing-dependent long-term potentiation was induced in layer V neurons from wild-type mice, the same stimulation protocol induced long-term depression in neurons from 5xFAD mice.

  6. X
    Cognitive Impairment at 24

    Impairments of spatial working memory and reduced anxiety emerge between 3 and 6 months and worsen with age.

Absent
No Data
  • Tangles at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid pathology starting at 2 months, including amyloid plaques. Accumulation of intraneuronal Aβ before amyloid deposition. Gliosis and synapse degeneration. Neuron loss in cortical layer V.

Age-dependent memory deficits, motor phenotype, and reduced anxiety.

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A7 APP transgenic

Observed
  1. X
    Plaques at 39

    These mice develop progressive amyloid deposition in the cerebral cortex by 9-12 months. By 21 months of age amyloid pathology is extensive.

Absent
No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish), APP T714I (Austrian) APP: Transgenic Alzheimer's Disease

Progressive amyloid deposition in the cerebral cortex by approximately 9-12 months.

Unknown.

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AAV-AD

Observed
  1. X
    Plaques at 128

    Amyloid plaques and cerebral amyloid angiopathy observed 30 months post-injection.

  2. X
    Changes in LTP/LTD at 40

    Deficits in LTP as Schaffer collateral-CA1 synapse at 10 months (8 months post-injection).  LTD similar to controls.

  3. X
    Cognitive Impairment at 40

    AAV-AD spent less time in the target quadrant of the Morris water maze in probe tests administered 3 and 5 days after training.

Absent
  • Gliosis at

    No astrogliosis observed up to 30 months post-injection.

No Data
  • Tangles at

    Immunostaining with monoclonal antibodies AT8 and AT100 suggests the presence of (pre)tangle-like structures 30 months post-injection.

  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), APP V717I (London), PSEN1 M146L (A>C) APP: Virus; PSEN1: Virus Alzheimer's Disease

Amyloid plaques and cerebral amyloid angiopathy observed 30 months post-injection. Anti-phospho-tau immunostaining suggests the presence of (pre)tangle-like structures. No astrogliosis seen up to 30 months post-injection.

Compared with control rats at 8 months post-injection, AAV-AD spent less time in the target quadrant of the Morris water maze in probe tests administered 3 and 5 days after training and less time in the center of the open field.

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AAV-sTREM2 5xFAD

Observed
  1. X
    Plaques at 28

    When examined at 7 months of age, amyloid plaque burdens in the hippocampus and cortex of AAV-sTREM2 5xFAD mice were about half those of 5xFAD mice injected with control vector.

  2. X
    Gliosis at 28

    The number of plaque-associated microglia was increased in AAV-sTREM2 5xFAD mice examined at 7 months of age.

  3. X
    Changes in LTP/LTD at 24

    Long-term potentiation at Shaeffer collateral-CA1 synapses is impaired in 5xFAD mice. AAV-mediated over expression of sTREM2 rescued LTP in AAV-sTREM2 5xFAD mice.

  4. X
    Cognitive Impairment at 24

    5xFAD mice show impaired learning and memory in the Morris water maze, but AAV-sTREM2 5xFAD mice performed as well as non-transgenic controls.

Absent
No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TREM2, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V TREM2: Virus; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

AAV-mediated over expression of sTREM2 decreased amyloid plaque burdens and increased numbers of plaque-associated microglia in the brains of 5xFAD mice.

5xFAD mice show impaired learning and memory in the Morris water maze, but AAV-sTREM2 5xFAD mice performed as well as non-transgenic controls.

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AAV-sTREM2 PS19

Observed
  1. X
    Synaptic Loss at 28

    AAV-mediated expression of sTREM2 protected against hippocampal synapse loss in PS19 mice.

  2. X
    Changes in LTP/LTD at 29

    LTP at Shaeffer collateral-CA1 synapses was slightly enhanced in hippocampal slices from 7-month-old AAV-sTREM2 PS19 mice, compared with PS19 mice who had received control vector.

  3. X
    Cognitive Impairment at 30

    AAV-mediated expression of sTREM2 improved performance of PS19 mice in the Morris water maze and Y-maze.

Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TREM2, MAPT MAPT P301S TREM2: Virus; MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease

AAV-mediated expression of sTREM2 protected against hippocampal synapse loss in PS19 mice.

AAV-mediated expression of sTREM2 improved performance of PS19 mice in the Morris water maze and Y-maze.

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Abca7*A1527G/APOE4/Trem2*R47H

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Abca7, APOE, Trem2 TREM2 R47H Abca7: Knock-In; APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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Abca7 KO/APOE4/Trem2*R47H

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Abca7, APOE, Trem2 TREM2 R47H Abca7: Knock-Out; APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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ADanPP

Observed
  1. X
    Plaques at 9

    Vascular amyloid deposits and punctate parenchymal aggregates first occur in the hippocampus and increase with age, spreading throughout the brain, including the cortex, amygdala, thalamus, and brainstem in hemizygous mice.

  2. X
    Gliosis at 17

    Astrogliosis and microgliosis increase with age and increasing ADan-amyloid deposition.

  3. X
    Cognitive Impairment at 78

    The only ages tested were 6 months and 18-20 months. Mice 18-20 months of age exhibited both motor and spatial learning defects in the Morris water maze, and increased anxiety in the open field test. No impairments were observed in 6 month-old mice.

Absent
  • Tangles at

    Absent.

  • Neuronal Loss at

    Absent.

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
ITM2B (BRI2) BRI2: Familial Danish Dementia (FDD) duplication ITM2B (BRI2): Transgenic Familial Danish Dementia, Alzheimer's Disease, Cerebral Amyloid Angiopathy

ADan deposition starts in the hippocampus and meningeal vessels at 2 months and increases with age. By 18 months, deposition is widespread. The majority of amyloid deposits are associated with the vasculature, where they destroy the integrity of the vessel wall and lead to microhemorrhages. Parenchymal amyloid plaques surrounded by microglia and dystrophic neurites are also present.

Impaired performance in Morris water maze, due to a combination of both motor deficits (i.e. reduced swim speed) and spatial learning deficits reported at 18-20 months. Open field test at 18-20 months also showed an anxiety-related phenotype.

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AD-BXD

Observed
  1. X
    Plaques at 24

    Transgenic AD-BXD mice develop amyloid plaques by 6 months of age, the earliest age examined. The extent of plaque deposition is strain-dependent.

  2. X
    Gliosis at 25

    Strain-dependent gliosis by 6 months. 

  3. X
    Cognitive Impairment at 60

    In the AD-BXD population as a whole, transgenic mice performed similarly to non-transgenic littermates in a contextual fear-conditioning test at 6 months, but were impaired at 14 months. The age of onset and severity of impairment are strain-dependent.

Absent
No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Transgenic AD-BXD mice develop amyloid plaques by 6 months of age, although the extent of plaque deposition is strain-dependent.

Transgenic AD-BXD mice exhibit cognitive deficits, assessed using contextual fear conditioning. The age of onset and severity of impairment are strain-dependent.

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APOE2 Knock-In, floxed (CureAlz)

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE APOE: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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APOE2 Knock-In (JAX)

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE APOE: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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APOE3 Knock-In, floxed (CureAlz)

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE APOE: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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APOE3 Knock-In (JAX)

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE APOE: Knock-In Alzheimer's Disease

No data.

No data.

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APOE3 Knock-In (Lamb)

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE APOE: Knock-In Alzheimer's Disease, Traumatic Brain Injury

Unknown.

Unknown.

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APOE4 Knock-In, floxed (CureAlz)

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE APOE: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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APOE4 Knock-In (JAX)

Observed
Absent
  • Cognitive Impairment at

    At 2 and 12 months of age, APOE4 KI mice perform similarly to wild-type mice in tests of locomotor activity, motor coordination, and working memory.

No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE APOE: Knock-In Alzheimer's Disease

No data.

No data.

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APP21

Observed
  1. X
    Neuronal Loss at 76

    Necrotic neurons in hippocampus and cortex of female rats.

  2. X
    Gliosis at 64

    Activated (MHCII-positive) microglia present in white matter tracts at 15 months.

  3. X
    Cognitive Impairment at 12

    Male rats show deficits in Morris water maze as early as 3 months of age. Females show deficits in Barnes maze at 14 months of age.

Absent
  • Plaques at

    Do not spontaneously develop amyloid pathology, but can serve as hosts for exogenously seeded amyloid deposits.

No Data
  • Tangles at

    “Flame-shaped” profiles in hippocampal neurons of 18- to 19-month-old female rats revealed by hematoxylin-and-eosin-staining.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish), APP V717F (Indiana) APP: Transgenic Alzheimer's Disease

No plaques to 30 months of age. Necrotic neurons in hippocampus and cortex by 19 months, in females; neuron loss not observed in cortices of 19-month males.

Male rats show deficits in Morris water maze as early as 3 months of age. Females show deficits in Barnes maze at 14 months of age.

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APP23

Observed
  1. X
    Plaques at 26

    Congophillic, dense-core amyloid plaques first appear at 6 months, and increase in size and number with age. Amyloid plaques can occupy more than 25% of the neocortex and hippocampus in 24 month-old mice (Sturchler-Pierrat et al., 1997; Calhoun et al., 1998).   

  2. X
    Neuronal Loss at 61

    Neuronal loss (14-28%) has been reported in the CA1 region of the hippocampus in 14-18 month old mice (Calhoun et al., 1998).     

  3. X
    Gliosis at 26

    Activated microglia in close proximity to dense amyloid plaques (Stalder et al., 1999). Upregulation of neuroinflammatory markers and activation of astrocytes and macrophages. Age-associated increase in components of the complement system, namely C1q and C3, at later ages (9 and 18 months, respectively) (Reichwald et al., 2009). 

  4. X
    Cognitive Impairment at 13

    Spatial memory defects in Morris Water maze at 3 months and progresses with age (Van dam et al., 2003; Kelly et al., 2003).

Absent
  • Tangles at

    Dystrophic neurites containing hyperphopshorylated tau surounds Aβ plaques, but no neurofibrillary tangles are observed (Sturchler-Pierrat et al., 1997).

  • Synaptic Loss at

    Neocortical synapses were examined in mice as old as 24 months of age; no evidence of alterations in the number of synapses or levels of synaptophysin were observed (Boncristiano et al., 2005).

  • Changes in LTP/LTD at

    LTP in the hippocampus and prefrontal cortex is normal at all ages studied: 3, 6, 9, 12, 18 and 24 months (Roder at al., 2003).

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish) APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy

Aβ deposits first observed at 6 months. Congophilic plaques increase in size and number with age and are surrounded by activated microglia, astrocytes, and dystrophic neurites containing hyperphosphorylated tau (although no neurofibrillary tangles). Neuronal loss in the CA1 region of the hippocampus. Mice also develop CAA, and microhemorrages occur at later ages.

Spatial memory defects in Morris Water maze at 3 months and progresses with age. Memory deficits in passive avoidance were observed in 25 month-old mice, but not at younger ages.

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APP23 x PS1-R278I

Observed
  1. X
    Plaques at 26

    By 6 months of age amyloid plaques accumulate in the cortex and hippocampus. A high percentage of plaques are thioflavin-S –positive cored plaques.

  2. X
    Gliosis at 39

    Astrocytosis in the vicinity of plaques in the hippocampus and cortex by 9 months.

  3. X
    Cognitive Impairment at 13

    Short-term memory deficits are apparent by 3 to 4 months as measured by the Y maze.

Absent
  • Tangles at

    Not observed.

No Data
  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 PSEN1 R278I APP: Transgenic; PSEN1: Knock-In Alzheimer's Disease

Amyloid deposition by 6 months of age in the cortex and hippocampus. Abundant reactive astrocytes in the vicinity of plaques. Elevated Aβ43 in the brain by 3 months. High density of cored plaques. Pyroglutamate Aβ (N3pE-Aβ) associated with amyloid plaques.

Short-term memory deficits apparent by 3-4 months as measured by the Y maze.

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APP751SL/PS1 KI

Observed
  1. X
    Plaques at 11

    Aβ deposition at 2.5 months compared to 6 months in APPSL mice. At 6 months, numerous compact Aβ deposits in the cortex, hippocampus, and thalamus, whereas in age-matched APPSL mice only very few deposits restricted mainly to the subiculum and deeper cortical layers. At 10 months, deposits increased in distribution, density, and size in both models (Casas et al., 2004).

  2. X
    Neuronal Loss at 23

    Some cell loss detectable as early as 6 months in female mice. At 10 months extensive neuronal loss (>50%) is present in the CA1/2 hippocampal pyramidal cell layer. SNeuronal loss also occurs in the frontal cortex and cholinergic system (Casas et al., 2004; Christensen et al., 2008; Christensen et al., 2010).

  3. X
    Gliosis at 11

    Astrogliosis occurs in parallel with Aβ deposition, starting around 2.5 months, and in proximity to Aβ-positive neurons (Wirths et al., 2010).

  4. X
    Synaptic Loss at 24

    At 6 months, levels of pre- and post-synaptic markers are reduced (Breyhan et al., 2009).

  5. X
    Changes in LTP/LTD at 28

    At 6 months there is a large reduction of long-term potentiation and disrupted paired pulse facilitation. No deficit at 4 months (Breyhan et al., 2009).

  6. X
    Cognitive Impairment at 27

    Age-dependent impairments in working memory as measured by the Y maze and T-maze continuous alternation task. No deficit at 2 months, but deficits at 6 and 12 months compared to PS1KI littermates (Wirths et al., 2008).

Absent
  • Tangles at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), APP V717I (London), PSEN1 M233T, PSEN1 L235P APP: Transgenic; PSEN1: Knock-In Alzheimer's Disease

Acceleration of extracellular Aβ deposition compared to the single transgenics. Age-dependent neuronal loss in the hippocampus with extensive neuronal loss in the CA1/2 at 10 months with detection as early as 6 months in female mice. Intraneuronal Aβ and thioflavin-S-positive deposits before neuronal loss. Astrogliosis in proximity of Aβ-positive neurons.

Age-dependent impairments in working memory as measured by the Y maze and T-maze continuous alternation task. No deficit at 2 months, but deficits at 6 and 12 months compared to PS1KI littermates.

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APPDutch

Observed
  1. X
    Gliosis at 126

    Microgliosis develops after the onset of CAA pathology and is prominent in areas adjacent to amyloid-laden vessels. There is also widespread activation of astrocytes in neocortical regions affected by CAA. These changes have been reported at 29 months of age, although the actual onset of gliosis may occur earlier than has been examined.

Absent
  • Plaques at

    No plaques are observed, but CAA develops at 22-24 months.

  • Tangles at

    Absent.

No Data
  • Neuronal Loss at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

  • Cognitive Impairment at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP E693Q (Dutch) APP: Transgenic Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type, Cerebral Amyloid Angiopathy, Alzheimer's Disease

Increased Aβ40/42 ratio. Extensive vascular Aβ deposition starting at 22-24 months appearing first in leptomeningeal vessels followed by cortical vessels, leading to smooth muscle cell degeneration, hemorrhages, and neuroinflammation. Parenchymal amyloid plaques are not observed. 

Unknown.

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APP E693Δ-Tg (Osaka)

Observed
  1. X
    Neuronal Loss at 104

    Neuronal loss, as measured by NeuN staining, was observed in the CA3 region of the hippocampus at 24 months of age. Neuronal loss was not detected in the cerebral cortex at this time.

  2. X
    Gliosis at 52

    At 12 months of age, microgliosis is seen in transgenic mice, as measured by the presence of Iba-1 staining in the hippocampus and cortex. Astrocytosis, as measured by GFAP-reactivity, increased starting around 18 months of age in these regions.

  3. X
    Synaptic Loss at 34

    Starting around eight months of age, transgenic mice exhibit a decrease in synaptic density in the CA3 region of the hippocampus as measured by synaptophysin staining.

  4. X
    Changes in LTP/LTD at 35

    By eight months of age, transgenic mice exhibit reduced short term plasticity as measured by paired-pulse facilitation in addition to reduced LTP as elicited by high frequency stimulation to the perforant pathway.

  5. X
    Cognitive Impairment at 36

    By 8 months of age, transgenic mice exhibit memory impairment in the Morris water maze compared to mice expressing equivalent levels of wild-type human APP.

Absent
  • Plaques at

    Extracelluar amyloid plaques are not observed out to 24 months; however, Aβ accumulates within neurons of the hippocampus and cerebral cortex starting around eight months of age.

  • Tangles at

    Overt tangle pathology is not observed out to 24 months of age, but abnormal tau phosphorylation is observed starting around eight months of age.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP E693del (Osaka) APP: Transgenic Alzheimer's Disease

Age-dependent accumulation of Aβ oligomers within hippocampal and cortical neurons, but negligible deposits of extracellular amyloid. Abnormal tau phosphorylation, but no overt tangle pathology. Synaptic loss and gliosis in hippocampus and cerebral cortex. Late neuronal loss in the CA3 region of the hippocampus.

Memory impairment by eight months as measured by the Morris water maze. Specifically, reduced spatial reference memory in the Morris water maze compared to mice expressing comparable levels of wild-type human APP.

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App knock-in (humanized Aβ)

Observed
Absent
  • Plaques at

    None observed at 3 months.

  • Tangles at

    None observed at 3 months.

  • Neuronal Loss at

    None observed at 3 months.

No Data
  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
App App: Knock-In Alzheimer's Disease

No plaques, neurofibrillary tangles, or neuron loss observed at three months, the oldest age reported.

Unknown.

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App knock-in (humanized Aβ)

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
App App: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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App knock-in (humanized Aβ) (Leuven)

Observed
Absent
  • Plaques at

    No plaques observed up to 2 years of age.

  • Tangles at

    No tangles observed up to 2 years of age.

No Data
  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
App App: Knock-In Alzheimer's Disease

No plaques or tangles were observed up to two years of age.

Unknown.

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App knock-in (humanized Aβ) (Leuven); Psen1 knock-in (M139T)

Observed
Absent
  • Plaques at

    No plaques observed up to 2 years of age.

  • Tangles at

    No tangles observed up to 2 years of age.

No Data
  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
App, Psen1 PSEN1 M139T App: Knock-In; Psen1: Knock-In Alzheimer's Disease

No plaques or tangles were observed up to 2 years of age.

Unknown.

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App knock‐in (Icelandic mutation and humanized Aβ)

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
App APP A673T (Icelandic) App: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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App knock‐in (Swedish mutation and humanized Aβ)

Observed
Absent
  • Plaques at

    None observed at 3 months.

  • Tangles at

    None observed at 3 months.

  • Neuronal Loss at

    None observed at 3 months.

No Data
  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
App APP K670_M671delinsNL (Swedish) App: Knock-In Alzheimer's Disease

No plaques, neurofibrillary tangles, or neuron loss observed at 3 months, the oldest age reported.

Unknown.

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App KO/APOE4/Trem2*R47H

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE, App, Trem2 TREM2 R47H APOE: Knock-In; App: Knock-Out; Trem2: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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APP NL-F Knock-in

Observed
  1. X
    Plaques at 26

    Homozygotes develop amyloid plaques starting at 6 months in the cortex and hippocampus. Heterozygotes develop amyloidosis after 24 months. Plaques contained Aβ1-42 and pyroglutamate Aβ (Aβ3(pE)-42); Aβx-40 was a minor species.

  2. X
    Gliosis at 26

    Microglia and activated astrocytes accumulate with age, starting around 6 months of age, concurrent with plaque formation.

  3. X
    Synaptic Loss at 39

    Reduced synaptophysin and PSD95 immunoreactivities associated with Aβ plaques at 9-12 months.

  4. X
    Cognitive Impairment at 78

    Memory impairment in homozygous mice at 18 months as measured by the Y maze test. APPNL/NL mice (with Swedish mutation only) were unimpaired at this age. No significant deficit was seen in the Morris water maze at 18 months.

Absent
  • Tangles at

    Absent; although elevated levels of phosphorylated tau are observed in dystrophic neurites around plaques.

  • Neuronal Loss at

    Absent.

No Data
  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish), APP I716F (Iberian) APP: Knock-In Alzheimer's Disease

Elevated Aβ peptides accumulating into plaques starting at 6 months. Microgliosis and astrocytosis, especially around plaques. Reduced synaptophysin and PSD-95 indicative of synaptic loss. No tangle pathology or neurodegeneration.

Memory impairment by 18 months as measured by the Y maze. No significant impairment in the Morris water maze.

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APP NL-G-F Knock-in

Observed
  1. X
    Plaques at 9

    Aggressive amyloidosis; plaques develop in homozygous mice starting at 2 months with near saturation by 7 months. Aβ deposition at 4 months in heterozygous mice. Cortical and subcortical amyloidosis present.

  2. X
    Gliosis at 9

    Microglia and activated astrocytes accumulate with age starting around 2 months, especially around plaques in a manner concurrent with plaque formation.

  3. X
    Synaptic Loss at 17

    Reduction of synaptophysin and PSD95 immunoreactivities associated with Aβ plaques in both cortical and hippocampal areas.

  4. X
    Cognitive Impairment at 26

    Memory impairment in homozygous mice by 6 months of age as measured by the Y maze.

Absent
  • Tangles at

    Absent; although phosphorylated tau is elevated in dystrophic neurites around plaques.

  • Neuronal Loss at

    Absent.

No Data
  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish), APP I716F (Iberian), APP E693G (Arctic) APP: Knock-In Alzheimer's Disease

Aggressive amyloidosis with deposition in the cortex beginning at 2 months and approaching saturation by 7 months. Aβ deposition in heterozygous mice at 4 months. Subcortical amyloidosis. Exacerbated microgliosis and astrocytosis compared to APPNL-F mice. Reduced synaptophysin and PSD-95 indicative of synaptic loss. No tangle pathology or neurodegeneration.

Memory impairment by 6 months as measured by the Y maze.

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App NL-G-F Knock-in Rat

Observed
  1. X
    Plaques at 4

    Amyloid plaques apparent as early as 1 month in homozygous knock-ins, 4 months in heterozygotes. Amyloid pathology progresses more rapidly in females than males.

  2. X
    Neuronal Loss at 52

    Reduced brain weight, fewer neurons in the hippocampus and cortex, and enlarged lateral ventricles seen at 12 months.

  3. X
    Gliosis at 24

    Astrogliosis and microgliosis, particularly pronounced around amyloid plaques, were observed in homozygous knock-in rats at 6 months of age. Gliosis was also seen in year-old heterozygotes.

  4. X
    Synaptic Loss at 24

    Decreased levels of the presynaptic marker synaptophysin and the postsynaptic marker PSD-95 in knock-in rats. Quantitative electron microscopy showed reductions in synaptic density, area, and perimeters in the hippocampus, entorhinal cortex and prefrontal cortex of knock-in brains.

  5. X
    Cognitive Impairment at 20

    Deficits in the Morris Water Maze task and a paired associate learning task as early as 5 and 7 months of age, respectively.

Absent
  • Tangles at

    No neurofibrillary tangles through 22 months of age, but increases in tau phosphorylation, aggregation, and conformational changes.

No Data
  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
App APP K670_M671delinsNL (Swedish), APP E693G (Arctic), APP I716F (Iberian) App: Knock-In Alzheimer's Disease

Amyloid plaques apparent as early as 1 month in homozygous knock-ins. No neurofibrillary tangles through 22 months of age, but increases in tau phosphorylation, aggregation, and conformational changes. Astrogliosis, microgliosis, synapse and neuron loss.

Deficits in the Morris Water Maze task and a paired associate learning task as early as 5 and 7 months of age, respectively.

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AppNL-G-F/MAPT double knock-in

Observed
  1. X
    Plaques at 8

    Plaques observed at 2 months.

  2. X
    Gliosis at 16

    Astrogliosis and microgliosis observed by 4 months.

  3. X
    Cognitive Impairment at 52

    Deficits in the Y-maze test of working memory at 12 months of age.

Absent
  • Tangles at

    No neurofibrillary tangles observed up to 24 months of age.

  • Neuronal Loss at

    No neurodegeneration observed up to 24 months of age.

No Data
  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
App, MAPT APP K670_M671delinsNL (Swedish), APP I716F (Iberian), APP E693G (Arctic) App: Knock-In; MAPT: Knock-In Alzheimer's Disease

Amyloid plaques, plaque-associated neuritic dystrophy, and neuroinflammation, similar to AppNL-G-F.

Deficits in the Y-maze test of working memory, similar to AppNL-G-F.

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APPPS1

Observed
  1. X
    Plaques at 6

    Aβ deposition begins at 6 weeks of age in the cortex and 3-4 months of age in the hippocampus (Radde et al., 2006).

  2. X
    Neuronal Loss at 74

    Global neuron loss is not observed, but modest neuron loss was found in the granule cell layer of the dentate gyrus and other subregions with high neuronal density in 17-month old animals (Rupp et al., 2011).

  3. X
    Gliosis at 6

    Activated microglia around Aβ deposits at 6 weeks as well as increased astrogliosis (Radde et al., 2006). Levels of CCL2 and TNFα increase at later ages (Lee et al., 2010).

  4. X
    Synaptic Loss at 10

    Dendritic spine loss around plaques reported to begin approximately 4 weeks after plaque formation and continue for several months (Bittner et al., 2012).

  5. X
    Changes in LTP/LTD at 35

    Hippocampal CA1 LTP normal at 4.5 months of age, but impaired at 8 and 15 months of age (Gengler et al., 2010).

  6. X
    Cognitive Impairment at 30

    Cognitive deficits in spatial learning and memory in the Morris water maze reported at 7 months (Serneels et al., 2009). Impaired reversal learning of a food-rewarded four-arm spatial maze task observed at 8 months (Radde et al., 2006).

Absent
  • Tangles at

    Phosphorylated tau-positive neuritic processes around plaques have been observed, but no mature tangles (Radde et al., 2006).

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1 L166P APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaque deposition starts at approximately 6 weeks in the neocortex. Amyloid deposits in the hippocampus appear at 3-4 months, and in the striatum, thalamus and brainstem at 4-5 months. Phosphorylated tau-positive neuritic processes have been observed in the vicinity of all congophilic amyloid deposits, but no fibrillar tau inclusions are seen.

 

Cognitive deficits in spatial learning and memory in the Morris water maze reported at 7 months. Impaired reversal learning of a food-rewarded four-arm spatial maze task at 8 months.

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APP+PS1

Observed
  1. X
    Plaques at 76

    Abundant plaques in hippocampus and subiculum, scattered plaques in cortex.

  2. X
    Neuronal Loss at 76

    Necrotic neurons in hippocampus and cortex.

  3. X
    Cognitive Impairment at 40

    Deficits in Barnes maze at 10 months.

Absent
No Data
  • Tangles at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), APP V717F (Indiana), PSEN1 L166P APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques, cerebral amyloid angiopathy, and necrotic neurons in hippocampus and cortex by 19 months of age.

Deficits in Barnes maze by 10 months of age.

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APP/PS1/rTg21221

Observed
  1. X
    Plaques at 35

    Cortical plaques observed between 8-10 months. Plaques larger than in control mice not expressing human tau.

  2. X
    Neuronal Loss at 36

    Neuronal loss observed adjacent to plaques relative to more distal areas.

  3. X
    Gliosis at 37

    Increased astrocytosis adjacent to plaques relative to more distal areas.

  4. X
    Synaptic Loss at 40

    Decreased synapse density adjacent to plaques relative to more distal areas.

Absent
  • Tangles at

    No tangles. Aggregates of misfolded and phosphorylated tau observed between 8-10 months.

No Data
  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1, MAPT APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 APP: Transgenic; PSEN1: Transgenic; MAPT: Transgenic Alzheimer's Disease

Tau accumulations, dystrophic neurites, astrocytosis, neuronal loss, and synapse loss were more pronounced adjacent to cortical plaques. Tangles were not observed.

No data.

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AppSAA Knock-in

Observed
  1. X
    Plaques at 16

    Amyloid plaques seen in AppSAA homozygous mice from 4 months of age and heterozygous mice at 16 months of age.

  2. X
    Gliosis at 16

    Plaque-associated microgliosis observed by 4 months of age.

Absent
  • Tangles at

    AT8-positive dystrophic neurites, but no neurofibrillary tangles, detected in AppSAA homozygous mice at 8 months of age.

No Data
  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
App APP K670_M671delinsNL (Swedish), APP E693G (Arctic), APP T714I (Austrian) App: Knock-In Alzheimer's Disease

Homozygotes: Amyloid plaques and plaque-associated microgliosis from 4 months of age; cerebral amyloid angiopathy and dystrophic neurites from 8 months of age. Heterozygotes: Amyloid plaques at 16 months of age.

Unknown.

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APPsw/0; Pdgfrβ+/-

Observed
  1. X
    Plaques at 39

    By 9 months of age APPsw/0;Pdgfrβ+/- mice have an elevated plaque load in the cortex and hippocampus compared with age matched APPsw/0;Pdgfrβ+/+. littermates. They also have extensive cerebral amyloid angiopathy.

  2. X
    Neuronal Loss at 39

    Progressive neuronal degeneration including reduced neurite density and reduced neuronal number in the cortex and hippocampus of APPsw/0; Pdgfrβ+/- mice at at nine months compared to age-matched APPsw/0; Pdgfrβ+/+ littermates.

  3. X
    Cognitive Impairment at 41

    At nine months, APPsw/0;Pdgfrβ+/- mice perform poorly on several hippocampal-dependent behavioral tests including burrowing, nest construction, and novel object recognition, compared with age-matched APPsw/0;Pdgfrβ+/+ littermates.

Absent
No Data
  • Tangles at

    Although mature neurofibrillary tangles were not observed by 9 months (the oldest age assessed), the mice develop significant tau pathology, including tau hyperphosphorylation in cortical and hippocampal neurons. Pre-tangle pathology is observed, including neuronal caspase-cleaved tau, and conformational changes as indicated by the conformation-specific antibody MC1.

  • Gliosis at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PDGFRB APP K670_M671delinsNL (Swedish) APP: Transgenic; PDGFRB: Knock-Out Alzheimer's Disease

Amyloid plaques; elevated brain interstitial human and murine Aβ due to reduced clearance of soluble Aβ, cerebral amyloid angiopathy, tau hyperphosphorylation and related pathology. Neurite loss and neuronal loss in the cortex and hippocampus.

Age-associated cognitive impairment as measured by hippocampal-dependent tasks, including nest building, burrowing, and novel object recognition.

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APPSwDI x NOS2 Knock-out

Observed
  1. X
    Plaques at 49

    Aβ deposits by 52 weeks. Particularly dense Aβ immunoreactivity in the subiculum and thalamus, including in the cerebral microvessels (Wilcock et al., 2008).

  2. X
    Tangles at 49

    Extensive tau pathology by 52 weeks, including intraneuronal aggregates of hyperphosphorylated tau. Increased phosphorylated tau in bigenic mice compared to APPSwDI mice (Wilcock et al., 2008).

  3. X
    Neuronal Loss at 52

    Significant neuron loss by 52 weeks in the hippocampus and subiculum, especially of neuropeptide Y neurons. Numerous Fluoro-Jade C+ neurons: 30% loss in the hippocampus, 35% loss in the subiculum (Wilcock et al., 2008).

  4. X
    Cognitive Impairment at 53

    Impairments in spatial memory by 52-56 weeks as measured by the radial arm maze and the Barnes maze. Bigenic mice more impaired than APPSwDI (Wilcock et al., 2008).

Absent
No Data
  • Gliosis at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, NOS2 APP K670_M671delinsNL (Swedish), APP E693Q (Dutch), APP D694N (Iowa) APP: Transgenic; NOS2: Knock-Out Alzheimer's Disease

Plaques especially in the thalamus and subiculum. Aggregated, hyperphosphorylated tau tangles. Neuronal loss especially of NPY neurons in the hippocampus and subiculum. More severe pathology than Tg-SwDI alone.

Severe learning and memory deficits. Impaired spatial memory compared to Tg-SwDI as measured by the radial arm maze and the Barnes maze at 52-56 weeks.

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APP(Swedish) (R1.40)

Observed
  1. X
    Plaques at 59

    By 13.5 months homozygous mice develop both parenchymal and vascular amyloid deposits which first appear in the frontal cortex. No Aβ deposition at 5 months (Lehman et al., 2003).

  2. X
    Gliosis at 61

    Reactive astrocytes and microglia in 14-16 month old animals (Kulnane et al., 2001).

Absent
  • Tangles at

    No mature tangles, but some changes in phosphorylated tau.

  • Changes in LTP/LTD at

    Absent.

No Data
  • Neuronal Loss at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Cognitive Impairment at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish) APP: Transgenic Alzheimer's Disease

By 14-16 months, homozygotes have diffuse and compact Aβ deposits in the frontal cortex, by 18-20 months plaques throughout the cortex and olfactory bulb with occasional deposits in the corpus callosum and hippocampus. No tangles, but some changes in phosphorylated tau. Reactive astrocytes and microglia by 14-16 months.

Unknown.

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APPSwe (line C3-3)

Observed
  1. X
    Plaques at 104

    Some plaque formation at advanced age (24-26 months) (Savonenko et al., 2003).

Absent
  • Cognitive Impairment at

    Normal reference and working memory up to 12-14 months on congenic background (Savonenko et al., 2003).

No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish) APP: Transgenic Alzheimer's Disease

Age-associated increase in Aβ40 and Aβ42 and some amyloid deposition at advanced age.

Congenic animals showed normal reference and working memory up to 12-14 months.

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APPSwe/PSEN1(A246E)

Observed
  1. X
    Plaques at 39

    By 9 months of age, amyloid plaques develop in the hippocampus and subiculum, later extending to the cortex (Borchelt et al., 1997). The striatum and thalamus are relatively spared out to 18 months of age. Amyloid pathology is more severe in female mice, with a greater amyloid burden measured at 12 and 17 months of age (Wang et al., 2003).

  2. X
    Gliosis at 52

    By one year of age, reactive gliosis is observed in the cortex and hippocampus and is associated with dystrophic neurites (Borchelt et al., 1997).

  3. X
    Cognitive Impairment at 48

    Age-associated cognitive impairment, as measured by the Morris water maze, was observed in 11 to 12-month-old males. Both acquisition and retention were impaired. No impairment at 3-4 months of age. At both time points mice performed normally on a position discrimination task in the T-maze (Puoliväli et al., 2002).

Absent
  • Tangles at

    Not observed.

  • Neuronal Loss at

    There was no difference in neuronal numbers in the cingulate cortex compared with wild-type mice (Xiang et al., 2002).

No Data
  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1 A246E APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques by 9 months, starting in the hippocampus and subiculum. Plaques later develop in the cortex; the striatum and thalamus are relatively spared. Amyloid pathology is more severe in females. Dystrophic neurites and gliosis in the cortex and hippocampus.

Poor nest building. Reduced retention in a learned passive avoidance task. Increased immobility time in forced swim task. Age-associated impairment in acquisition and retention in the Morris water maze. No impairment in a position discrimination T-maze task.

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APPSwe/PSEN1dE9 (C3-3 x S-9)

Observed
  1. X
    Plaques at 26

    Plaques are present in the hippocampus and cortex by 6 months of age.

  2. X
    Cognitive Impairment at 78

    Age-related cognitive deficits. Episodic memory appears to be more sensitive than reference memory. No differences at 6 months of age, but detectable at 18 months (Savonenko et al., 2005).

Absent
  • Tangles at

    Not observed.

No Data
  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Elevated Aβ42 and plaques in the hippocampus and cortex. No tangles. Reduced cholinergic markers.

Age-related cognitive deficits; episodic memory more sensitive than reference memory. No differences at 6 months, but detectable at 18 months.

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APPswe/PSEN1dE9 (C57BL6)

Observed
  1. X
    Plaques at 16

    Amyloid plaques begin to emerge in the cortex at about 4 months of age and in the hippocampus at about 6 months.

  2. X
    Gliosis at 17

    Plaque-associated astrogliosis and microgliosis are evident by 4 and 8 months, respectively.

  3. X
    Synaptic Loss at 18

    Synapse loss in the hippocampus occurs by 4 months.

  4. X
    Cognitive Impairment at 40

    Deficits in the Morris water maze emerge between 6 and 10 months and worsen with age.

Absent
  • Tangles at

    Not observed.

  • Neuronal Loss at

    Neuron loss has not been observed in mice up to 12 months of age.

No Data
  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques begin to emerge in the cortex at about 4 months of age and in the hippocampus at about 6 months. Gliosis and dystrophic neurites are associated with plaques. Amyloid angiopathy has been observed in the retina.

Hyperactivity is apparent by 6 months. Deficits in the Morris water maze emerge between 6 and 10 months and worsen with age.

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APPswe/PSEN1dE9 (line 85)

Observed
  1. X
    Plaques at 26

    Occasional Aβ deposits can be found by 6 months, with abundant plaques in the hippocampus and cortex by 9 months (Jankowsky et al., 2004) and a progressive increase in plaques up to 12 months (Garcia-Alloza et al., 2006).

  2. X
    Neuronal Loss at 35

    Neuronal loss observed adjacent to plaques relative to more distal areas.

  3. X
    Gliosis at 26

    Minimal astrocytosis at 3 months; significant astrocytosis by 6 months, especially in areas around plaques. Extensive GFAP+ staining at 15 months and later throughout the cortex (Kamphuis et al., 2012).

  4. X
    Synaptic Loss at 17

    In the B6 congenic mice, age-dependent loss of synaptophysin, synaptotagmin, PSD-95, and Homer immunoreactivity in the hippocampus by 4 months (Hong et al., 2016).

  5. X
    Changes in LTP/LTD at 13

    Transient long-term potentiation (t-LTP) is reduced by 3 months. The degree of impairment is not related to age from 3 to 12 months (Volianskis et al., 2008).

  6. X
    Cognitive Impairment at 52

    Impairment in the Morris water maze at 12 months, specifically during acquisition of the hidden platform sub-task and the probe trial, but not in the visible platform test (Lalonde et al., 2005). At 13 months the mice commit more errors in the Morris water maze, but not at 7 months (Volianskis et al., 2008).

Absent
  • Tangles at

    Not observed.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Occasional Aβ deposits by 6 months with abundant plaques in the hippocampus and cortex by 9 months and a progressive increase in plaques up to 12 months. No tangles. Decrease in synaptic markers and increase in complement immunoreactivity.

Cognitive impairment (e.g., deficits in spatial memory and contextual memory). Changes in spontaneous behavior (e.g., nest-building, burrowing).

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APP(V642I)KI

Observed
  1. X
    Cognitive Impairment at 117
    Impairments at the water finding task at age 27-29 months, a test of long-term memory. No differences in the open field test of the elevated plus maze indicating no difference in general behavioral patterns, activity level, or emotional state.
Absent
  • Plaques at

    Absent.

  • Tangles at

    Absent.

  • Neuronal Loss at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP V717I (London) APP: Transgenic Alzheimer's Disease

Increased Aβ42(43) relative to Aβ40 at 29 months, but without neuritic plaques, neurofibrillary tangles, massive neuronal loss, or brain atrophy.

At 27-29 months mice displayed long-term memory deterioration. Acquisition of spatial memory is slightly affected, but no deterioration in short-term working memory. No difference in open field test or elevated plus maze suggesting no difference in overall behavioral patterns or activity levels.

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APP(V717I)

Observed
  1. X
    Plaques at 43

    Plaques start in the cortex and subiculum at ~10 months. Diffuse amyloid deposits and compact neuritic plaques at 13-18 months especially in the hippocampus and cortex, with occasional deposits in the thalamus and fimbria, external capsule, pontine nuclei, and white matter (Moechars et al., 1999). Prominent amyloid deposits in brain vessels after 15 months (Van Dorpe et al, 2000).

  2. X
    Gliosis at 43

    GFAP, microglial activation, and other markers of brain inflammation are elevated by 10 months.

  3. X
    Changes in LTP/LTD at 26

    Significant deficit in LTP in CA1 region of the hippocampus at 6 months.

  4. X
    Cognitive Impairment at 26

    From the age of 6 months, spatial and non-spatial orientation and memory deficits by Morris water maze and other tests. Also deficits in associative learning.

Absent
  • Tangles at

    Dystrophic neurites containing hyperphosphorylated tau, but no tangle pathology.

  • Neuronal Loss at

    Absent.

No Data
  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP V717I (London) APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy

Plaques start in the subiculum, spreading to the frontal cortex as dense and diffuse aggregates. Prominent amyloid deposits in brain vessels after 15 months. Microbleeds. Amyloid-associated inflammation. CSF Aβ42/Aβ40 ratio decreases from 15 months. Dystrophic neurites containing hyperphosphorylated tau, but no tangle pathology.

From the age of 6 months, spatial and non-spatial orientation and memory deficits by Morris water maze. Impaired associative learning. Increased agitation/anxiety from 8 weeks. Reduced ambulation, especially with age. Hyperactivity and aggression.

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APP(V717I) x PS1(A246E)

Observed
  1. X
    Plaques at 17

    Plaques start in cortex, hippocampus and subiculum at 4-6 months.

  2. X
    Gliosis at 20

    Elevated GFAP, microglial activation, and other markers of brain inflammation increase as of 4.5 months.

  3. X
    Changes in LTP/LTD at 26

    Significant deficit in LTP in CA1 region of the hippocampus at 6 months.

  4. X
    Cognitive Impairment at 22

    From the age of 5 months, spatial and non-spatial orientation and memory deficits by Morris water maze and other tests. Also deficits in associative learning.

Absent
  • Tangles at

    Dystrophic neurites containing hyperphosphorylated murine tau, but no tangle pathology.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP V717I (London), PSEN1 A246E APP: Multi-transgene; PSEN1: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy

Soluble, oligomeric Aβ at 2 months and increases with age. Amyloid plaques at 6-9 months, earlier than APP(V717I) single transgenics. Plaques start in the subiculum and spread to the frontal cortex. Amyloid-associated inflammation. CAA pathology at 8 months; microbleeds at 12-15 months. Dystropic neurites containing hyperphosphorylated tau, but no tangle pathology.

From the age of 5 months, spatial and non-spatial orientation and memory deficits by Morris Water Maze. Impaired associative learning, hyperactivity, anxiety, and aggression.

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Arc48 (APPSw/Ind/Arc)

Observed
  1. X
    Plaques at 9

    Parenchymal neuritic plaques by 2 months with prominent plaque deposition in the hippocampus by 3-4 months. Abundant mature thioflavin-S positive plaques with dystrophic neurites by 10-12 months (Cheng et al., 2007).

  2. X
    Gliosis at 13

    Reactive astrocytosis at 3-4 months in the dentate gyrus as demonstrated by GFAP immunoreactivity (Cheng et al., 2007).

  3. X
    Cognitive Impairment at 13

    At 3-4 months the Arc48 mouse was able to learn a task involving escape to a cued platform in the Morris water maze, but were impaired in the ability to use extramaze cues to navigate to the hidden platform (Cheng et al., 2007).

Absent
  • Tangles at

    Absent.

No Data
  • Neuronal Loss at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish), APP V717F (Indiana), APP E693G (Arctic) APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy

Parenchymal neuritic plaques by 2 months accompanied by dystrophic neurites. Prominent hippocampal Aβ deposition by 3-4 months. Relatively low Aβ42/Aβ40 ratio. Comparable cerebrovascular amyloid deposition to J20.

At 3-4 months the Arc48 mouse was able to learn a task involving escape to a cued platform in the Morris water maze, but had an impaired ability to use extramaze cues to navigate to the hidden platform.

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ArcAβ

Observed
  1. X
    Plaques at 39

    Between 9 and 15 months of age β-amyloid plaques became prominent. Plaques had a characteristic dense core morphology which differed from the cotton wool-like structure of plaques seen with the Swedish mutation alone (Knobloch et al., 2007).

  2. X
    Changes in LTP/LTD at 15

    LTP is severely impaired in slices from 3.5 and 7.5 month old mice. LTP and basal synaptic transmission were normal in slices from one month old mice (Knobloch et al., 2007).

  3. X
    Cognitive Impairment at 26
    Cognitive impairment measured from the age of 6 months in the Morris water maze and Y-maze, as well as in active avoidance behavior (Knobloch et al., 2007).
Absent
  • Tangles at

    Absent.

No Data
  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish), APP E693G (Arctic) APP: Transgenic Alzheimer's Disease At 6 months intracellular punctate deposits of Aβ abundant in cortex and hippocampus, but overt β-amyloid plaques not apparent until 9-15 months. Severe CAA also present at this age with dense Aβ aggregates in blood vessels walls and spreading into the parenchyma.

Cognitive impairments from the age of 6 months measured in the Morris water maze and Y-maze.

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ARTE10

Observed
  1. X
    Plaques at 13

    Robust and reliable plaque pathology as early as 3 months in homozygotes, 5 months in hemizygotes. Plaques start in the anterior neocortex and subiculum, spreading to other brain regions (e.g. hippocampus, thalamus, amygdala). Congophilic dense-core plaques are abundant, with lower levels of diffuse plaques and some cerebral amyloid angiopathy.

  2. X
    Gliosis at 22

    Glial activation, including reactive astrocytes and activated microglia, is present in areas around plaques by 5 months of age in homozygous animals, later in hemizygotes.

  3. X
    Synaptic Loss at 13

    Decreased expression of synaptophysin mRNA in the brain by 3-4 months of age in both hemizygous and homozygous animals.

  4. X
    Cognitive Impairment at 52

    Select, paradigm-dependent, deficits in learning and memory, especially episodic memory, by 12 months in homozygous and hemizygous mice.

Absent
  • Tangles at

    No tangles or neuropil threads, but some hyperphosphorylated tau by eight months in dystrophic neurites.

  • Neuronal Loss at

    Outright neuronal loss has not been documented, but substantial degeneration of dendritic arbors occurs by 10-14 months of age in hippocampal neurons.

No Data
  • Changes in LTP/LTD at

    Unknown; however, hippocampal neurons exhibit substantial changes in electrophysiological properties by 10-14 months of age, including hyperexcitability in the form of increased firing of action potentials and a more efficient transition from solitary firing to bursting.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1 M146V APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Robust early plaque development (by 3 months in homozygotes, 5 months in hemizygotes), predominantly congophilic dense-core amyloid plaques surrounded by dystrophic neurites and gliosis. Some diffuse plaques and cerebral amyloidosis. No tau tangles. Neurons have reduced dendritic length, surface area, and branches.

Age-related learning and memory deficits, especially episodic memory, in select paradigm-specific tasks by 12 months.

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Atg16LΔWD

Observed
  1. X
    Neuronal Loss at 104

    Apparent neuron loss in hippocampi of 2-year-old mice (fewer neurons, increased levels of cleaved caspase-3, and increased numbers of TUNEL-positive neurons).

  2. X
    Gliosis at 104

    Microgliosis in the hippocampi of 2-year-old mice.

  3. X
    Changes in LTP/LTD at 104

    Impaired long-term potentiation at CA3-CA1 synapses.

  4. X
    Cognitive Impairment at 104

    Deficits in the sucrose preference test, spontaneous alternation in the Y-maze, and novel object recognition test.

Absent
  • Plaques at

    Intracellular and extracellular Aβ deposits, but no dense-core plaques, in 2-year-old mice.

No Data
  • Tangles at

    No data.

  • Synaptic Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Atg16l1 Atg16l1: Knock-Out Alzheimer's Disease

Intracellular and extracellular Aβ deposits, but no dense-core plaques. Microgliosis and neuron loss in 2-year-old mice.

Deficits in the sucrose-preference test, spontaneous alternation in the Y-maze, and novel object recognition test.

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BACE1 cKO (Hu, Yan) X 5xFAD

Observed
  1. X
    Plaques at 11

    Accumulate up to day 120, but to a lesser degree than in control 5xFAD, then recede thereafter.

  2. X
    Gliosis at 11

    Reactive astrocytes and microglia accumulate up to day 120, but to a lesser degree than in control 5xFAD, then recede thereafter.

  3. X
    Changes in LTP/LTD at 40

    Deficit in LTP at Schaffer collateral–CA1 synapses, but less severe than in control 5xFAD mice.

Absent
  • Cognitive Impairment at

    Cued and contextual fear conditioning normal, tested at eight to 10 months of age.

No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Bace1, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V Bace1: Conditional Knock-out; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques, reactive astrocytes and microglia, and dystrophic neurites accumulate up to day 120, but to a lesser degree than in control 5xFAD (5xFAD mice homozygous for a floxed Bace1 gene), then recede thereafter.

Normal contextual and cued fear conditioning, tested at 8 to 10 months of age.

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Bace1 conditional knock-out (adult, whole body) (Vassar)

Observed
Absent
  • Changes in LTP/LTD at

    LTP at Schaffer collateral–CA1 synapses was similar in slices obtained from 12-month BACE1-deficient and control mice.

  • Cognitive Impairment at

    Normal learning and memory in the Morris water maze, normal alternation in the Y-maze test of working memory, and normal cued and contextual fear conditioning when tested at 9 months of age.

No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Bace1 Bace1: Conditional Knock-out Alzheimer's Disease

Defects in axonal organization.

Normal learning and memory in the Morris water maze, normal alternation in the Y-maze test of working memory, and normal cued and contextual fear conditioning; possible hyperactivity in novel situations.

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BACE1 conditional knock-out (Hu, Yan)

Observed
  1. X
    Changes in LTP/LTD at 40

    Long-term potentiation at Schaffer collateral–CA1 synapses impaired in slices obtained from 10- to 12-month-old mice.

Absent
  • Plaques at

    Not observed.

  • Tangles at

    Not observed.

  • Neuronal Loss at

    Not observed.

  • Gliosis at

    No astrogliosis at 1-2 months.

  • Cognitive Impairment at

    Contextual and cued fear conditioning normal at 8-10 months.

No Data
  • Synaptic Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Bace1 Bace1: Conditional Knock-out Alzheimer's Disease

No gross morphological changes observed.

BACE1-deficient mice and Bace1fl/fl mice performed similarly in tests of contextual and cued fear conditioning at 8 to 10 months of age.

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Bace1 conditional knock-out (neonatal, forebrain) (Vassar)

Observed
  1. X
    Cognitive Impairment at 24

    Delayed learning, but normal memory, in the Morris water maze; normal alternation in the Y-maze test of working memory, normal cued and contextual fear conditioning.

Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Bace1 Bace1: Conditional Knock-out Alzheimer's Disease

Hypomyelination and defects in axon organization.

Delayed learning, but normal memory, in the Morris water maze; normal alternation in the Y-maze test of working memory, normal cued and contextual fear conditioning. Hyperactivity in when placed in novel environments.

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Bace1 conditional knockout (Tesco)

Observed
  1. X
    Changes in LTP/LTD at 60

    Deficit in long-term potentiation at Schaffer collateral–CA1 synapses in slices from 14-month-old animals that had received tamoxifen between 8 and 12 weeks of age.

Absent
  • Cognitive Impairment at

    Animals that had received tamoxifen between 8 and 12 weeks of age were tested at 4–5 or 12–14 months. Tamoxifen-treated mice performed similarly to vehicle-treated controls in the Y-maze, contextual fear conditioning, pre-pulse inhibition, open field, and light-dark transition tests.

No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Bace1 Bace1: Conditional Knock-out Alzheimer's Disease

None observed: hippocampal mossy fiber organization and sciatic-nerve myelination were normal.

Performed similarly to controls in a battery of tests (Y-maze, contextual fear conditioning, pre-pulse inhibition, open field, and light-dark transition task).

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BRI-Aβ42 (BRI2-Aβ42)

Observed
  1. X
    Plaques at 13

    Detergent-insoluble amyloid-β and cored plaques as early as three months in the cerebellum. Variable forebrain pathology later with extracellular Aβ plaques in the hippocampus and entorhinal/piriform cortices by 12 months. Extensive congophillic amyloid angiopathy.

  2. X
    Gliosis at 13

    Plaque-associated reactive gliosis as measured by GFAP immunostaining.

Absent
  • Tangles at

    Absent.

  • Neuronal Loss at

    Absent.

  • Cognitive Impairment at

    On a mixed (C57/B6//C3H) background hemizygous mice have intact cognition as measured by fear conditioning at 12 months and 14-17 months despite accumulating amyloid.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy

Detergent-insoluble amyloid-β appearing with age and cored plaques as early as 3 months in the cerebellum. Variable forebrain pathology later with extracellular Aβ plaques in the hippocampus and entorhinal/piriform cortices at 12 months. Age-associated congophillic amyloid angiopathy. No tangles or neuronal loss.

On a mixed (C57/B6//C3H) background hemizygous mice have intact cognition as measured by fear conditioning at 12 months and 14-17 months despite accumulating amyloid.

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CAST.APP/PS1

Observed
  1. X
    Plaques at 32

    Thioflavin S-positive amyloid plaques are present in the cortex and hippocampus by 8 months of age, with more severe plaque pathology in females than in males.

  2. X
    Neuronal Loss at 34

    Compared with their non-transgenic littermates, CAST.APP/PS1 mice have fewer neurons in area CA1 of the hippocampus. Cortical neuron numbers do not differ between the genotypes.

  3. X
    Gliosis at 33

    Plaque-associated microgliosis observed by 8 months.

  4. X
    Cognitive Impairment at 31

    Deficits in short-term memory by 8 months in males (data from females unavailable).

Absent
  • Tangles at

    Not observed.

No Data
  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques, plaque-associated gliosis, cerebral amyloid angiopathy; possible neuron loss in hippocampal area CA1.

Transgenic mice are hyperactive. Working memory (spontaneous alternation in the Y-maze) is normal at 7 to 8 months, but short-term memory (tested in the Y-maze) is impaired in males (data from females is not available, as wild-type females are unable to perform this test).

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Ceacam1 KO/APOE4/Trem2*R47H

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE, Ceacam1, Trem2 TREM2 R47H APOE: Knock-In; Ceacam1: Knock-Out; Trem2: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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Clasp2*L163P/APOE4/Trem2*R47H

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Clasp2, APOE, Trem2 TREM2 R47H Clasp2: Knock-In; APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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Dp(16)1Yey/+

Observed
  1. X
    Neuronal Loss at 56

    Loss of vulnerable neurons (neurons in layer II of entorhinal cortex, catecholaminergic neurons in the locus coeruleus and the basal forebrain at advanced ages.

  2. X
    Synaptic Loss at 37

    Critical synaptic proteins were altered, including syntaxin 1A and SNAP25.

  3. X
    Changes in LTP/LTD at 8

    Magnitude of hippocampal LTP following theta burst stimulation is lower than the WT controls around 2-4 months of age.

  4. X
    Cognitive Impairment at 9

    Cognitive impairments were observed at 2-4 months of age, as well as at more advanced ages.

Absent
  • Plaques at

    None.

  • Tangles at

    None.

No Data
  • Gliosis at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Multi-transgene Down's Syndrome, Alzheimer's Disease

Neuronal loss in the entorhinal cortex, locus coeruleus, and the basal forebrain magnocellular complex; increased tau pathology and increased astrocyte and microglia levels.

Impairments in contextual memory, spatial learning, novel object recognition memory, and vocalizations.

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Dp1Tyb

Observed
  1. X
    Gliosis at 14

    Increased density of microglia in the hippocampus at 14 weeks of age.

  2. X
    Cognitive Impairment at 8

    Exploratory behavior is impaired at 8 weeks of age. Fear memory is impaired at 10 months. Spatial working memory is impaired at 3-months of age.

Absent
  • Plaques at

    No amyloid-β plaque deposition is observed in hippocampus at 12-months of age.

  • Tangles at

    Not observed.

No Data
  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Knock-In Down's Syndrome, Alzheimer's Disease

No amyloid plaques. At 14 weeks, smaller and rounder brain, reduced medial prefrontal cortex and dorsal hippocampus volumes, reduced density of neurons, and increased density of microglia in the hippocampus. Altered hippocampal metabolites including glutamine and the glutamine/glutamate ratio. Reduced IB4 neurons in the DRG.

Exploratory behavior is impaired at 8 weeks of age. Fear memory is impaired at 10 months. Motor function is impaired at 12-15 weeks of age. Sleep architecture is disrupted at 16-weeks of age. Spatial working memory is impaired at 3-months of age.

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Dp9Tyb

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Down's Syndrome, Alzheimer's Disease

Unknown.

No locomotor defects as assessed by Rotarod at 12 weeks of age.

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E2FAD

Observed
  1. X
    Plaques at 17

    Plaques develop in the subiculum and deep cortical layers by 4 months.

  2. X
    Gliosis at 26

    Microgliosis and astrocytosis in the subiculum and cortex at 6 months.

  3. X
    Synaptic Loss at 17

    Protein levels of  NMDA receptor subunits decreased from 2 to 6 months.

Absent
No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    E2FAD mice had performance in learning and memory tasks comparable to E3FAD animals and better than E4FAD mice.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V APOE: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques starting at 4 months and increasing with age. Gliosis and loss of synaptic proteins.

In the Y maze and Morris water maze, E2FAD mice performed better than E4FAD mice, and were comparabile to E3FAD mice.

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E3FAD

Observed
  1. X
    Plaques at 17

    Plaques develop in the subiculum and deep cortical layers by 4 months.

  2. X
    Gliosis at 26

    Microgliosis and astrocytosis in the subiculum and cortex at 6 months.

  3. X
    Synaptic Loss at 17

    Protein levels of  NMDA receptor subunits decreased from 2 to 6 months.

Absent
No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    E3FAD mice had performance in learning and memory tasks comparable to E4FAD and E2FAD animals.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V APOE: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques starting at 4 months and increasing with age. Gliosis and loss of synaptic proteins.

In the Y maze and Morris water maze E3FAD mice performed better than E4FAD mice, and were comparabile to E2FAD mice.

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E4FAD

Observed
  1. X
    Plaques at 17

    Plaques develop in the subiculum and deep cortical layers by 4 months.

  2. X
    Gliosis at 26

    Microgliosis and astrocytosis in the subiculum and cortex at 6 months.

  3. X
    Synaptic Loss at 17

    Decreased protein levels of PSD95 and NMDA receptor subunits by 4 months.

  4. X
    Cognitive Impairment at 8

    Modest learning deficits in the Morris water maze by 2 months. Progressive decrease in performance on learning and memory tasks. 

Absent
No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V APOE: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques starting at 4 months and increasing with age. Gliosis and loss of synaptic proteins. 

Age-dependent learning and memory deficits in the Y maze and Morris water maze.

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hAbeta/APOE4/Trem2*R47H (LOAD2)

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE, APP, Trem2 TREM2 R47H APOE: Knock-In; APP: Knock-In; Trem2: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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hAbeta-loxP-KI

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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hAβ-KI

Observed
  1. X
    Synaptic Loss at 78

    Fewer synaptophysin-immunoreactive puncta, but similar numbers of PSD95-immunoreactive puncta, in knock-in mice compared with wild-type mice.

  2. X
    Changes in LTP/LTD at 78

    Impaired theta-burst-induced LTP at Schaffer collateral-CA1 synapses, by 18 months of age.

  3. X
    Cognitive Impairment at 40

    Differed from wild-type mice in the contextual fear conditioning test by 10 months of age and in the novel object recognition task by 14 months.

Absent
  • Plaques at

    No plaques observed through 22 months of age, using immunohistochemical, thioflavin-S or Congo red stains.

  • Neuronal Loss at

    Neuron numbers in hippocampal CA1 were similar in 22-month hAβ-KI and wild-type mice, although hippocampal volume was decreased in the knock-in mice.

  • Gliosis at

    Neither microgliosis nor astrogliosis was observed through 22 months of age.

No Data
  • Tangles at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
App App: Knock-In Alzheimer's Disease

No amyloid plaques observed through 22 months of age. Accelerated formation of OC-immunoreactive and Periodic Acid Schiff-positive granules.

Differed from wild-type mice in the contextual fear conditioning test by 10 months of age and in the novel object recognition task by 14 months.

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hCR1 KI on APOE4/Trem2

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Cr2, CR1, CR2, APOE, Trem2 TREM2 R47H Cr2: Knock-Out; CR1: Knock-In; CR2: Knock-In; APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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htau

Observed
  1. X
    Tangles at 39

    Aggregated tau and paired helical filaments detectable at nine months by immunoelectron microscopy, although paired helical filaments of aggregated insoluble tau can be isolated from brain tissue as early as two months. Tau first redistributes from axons to cell bodies. Hyperphosphorylated tau begins to accumulate by six months, and increases further by 13 and 15 months (Andorfer et al., 2003).

  2. X
    Neuronal Loss at 43

    Decrease in cortical thickness and reduced cell number between 10 and 14 months of age. Increased ventricle size increased from age eight months to 18 months. Decrease in the thickness of the corpus callosum (Andorfer et al., 2005).

  3. X
    Changes in LTP/LTD at 52

    In hippocampal slices, LTP induced by high frequency stimulation (HFS) was normal at four months but abolished by 12 months. LTP induced by theta burst stimulation (TBS) was normal at both ages. Paired-pulse ratio (PPR) was unaffected at four months, but increased at 12 months compared with controls, suggesting a decrease in probability of transmitter release (Polydoro et al., 2009).

  4. X
    Cognitive Impairment at 26

    Abnormal spatial learning in six-month-old mice compared with control mice (Phillips et al., 2011). Normal object recognition and spatial learning and memory by MWM at four months, but deficits by 12 months (Polydoro et al., 2009). Impaired burrowing relative to control mice occurs by four months (Geiszler et al., 2016).

Absent
No Data
  • Gliosis at

    Unknown.

  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT: Knock-Out; MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia

Age-associated tau pathology, including redistribution of tau to cell bodies and dendrites, phosphorylated tau, accumulation of aggregated paired helical filaments, and ultimately thioflavin-S positive neurofibrillary tangles. Pathology most severe in neocortex and hippocampus, and minimal in the brain stem and spinal cord. Some neuronal loss.

Normal object-recognition memory and spatial learning/memory (as assessed by the Morris Water Maze) at four months, but impaired at 12 months (Polydoro et al., 2009). 

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hTau-A152T

Observed
  1. X
    Neuronal Loss at 87

    Neuron loss in the hippocampus was observed by 20 months.

  2. X
    Gliosis at 17

    Astrocytosis, but no differences in microglia.

  3. X
    Cognitive Impairment at 74

    In the Morris water maze, performance was impaired after 17 months of age. Nest building was impaired at 10-14 months. Social interaction, anxiety, exploratory behavior, and motor functions were unaltered.

Absent
  • Tangles at

    Abnormal accumulations of soluble tau were observed, but not tangles or tangle-like structures.

  • Changes in LTP/LTD at

    Unchanged at 20 months.

No Data
  • Plaques at

    No data.

  • Synaptic Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT A152T MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy

Tangles or dense tau inclusions not observed. Abnormal accumulations of soluble tau. Age-dependent neuronal loss was observed in the hippocampus.

Age-dependent learning and memory deficits in the Morris water maze. Nest building impaired. Social interaction, anxiety, exploratory behavior, and motor functions were normal.

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hTau-AT (hTau40-AT)

Observed
  1. X
    Tangles at 13

    Tangles in hippocampus, cortex, and spinal cord starting at 3 months with age-dependent increases. Hyperphosphorylation, conformation changes, and mislocalization.

  2. X
    Neuronal Loss at 52

    Neuron loss in the hippocampus and cortex at 12 months.

  3. X
    Gliosis at 43

    Astrocytosis and microgliosis at 10 months.

  4. X
    Synaptic Loss at 87

    Synaptophysin, but not PSD95, decreased in hippocampus and cortex at 12 months. By Golgi staining, spines unchanged in CA1 at 10 months, increased in CA3 at 12 months, and decreased in CA1 and CA3 at 16 months.

  5. X
    Cognitive Impairment at 70

    No change at 10 months but at 16 months deficits in learning and memory (Morris water maze).

Absent
  • Changes in LTP/LTD at

    Unchanged at 12 months.

No Data
  • Plaques at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT A152T MAPT: Knock-In Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy

Tangles in hippocampus, cortex, and spinal cord at 3 months with age-dependent increases. Tau hyperphosphorylation, conformation changes, and mislocalization observed. Age-dependent loss of synapses.

Age-dependent learning and memory deficits in the Morris water maze. Motor functions normal.

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hTau.P301S

Observed
  1. X
    Tangles at 17

    Neurofibrillary tangles detected as early as 4 months of age.

  2. X
    Neuronal Loss at 13

    Neuronal loss starting at 3 months. Loss is especially prominent in the spinal cord with notable loss of superficial cortical neurons as well (Hampton et al., 2010).

  3. X
    Gliosis at 22

    Astrocytosis, as measured by GFAP reactivity, in 6 month-old animals. Microglial activation in the brain stem and spinal cord of 5 month-old animals by OX42 staining (Bellucci et al., 2004).

  4. X
    Cognitive Impairment at 11

    Memory deficit starting at 2.5 months as assessed by the Morris water maze (Xu et al., 2014), but no deficit at 2 months (Scattoni et al., 2010).

Absent
  • Plaques at

    Absent.

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT P301S MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy

Age-dependent hyperphosphorylation of tau and conformational changes leading to neurofibrillary tanglelike pathology in the cerebral cortex, hippocampus, brain stem, and spinal cord. Neurodegeneration, especially in the spinal cord, accompanied by astrocytosis.

Early motor impairment, including abnormal clasping and rotarod deficit at 4 months, with nearly complete deficit at 5 months. Deficits progress to severe paraparesis. Disinhibition and hyperactivity at 2 to 3 months.

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hTREM2-KI

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TREM2 TREM2: Knock-In Alzheimer's Disease

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hTREM2-R47H_KI

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TREM2 TREM2 R47H TREM2: Knock-In Alzheimer's Disease

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Il1rap KO/APOE4/Trem2*R47H

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE, Il1rap, Trem2 TREM2 R47H APOE: Knock-In; Il1rap: Knock-Out; Trem2: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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J20 (PDGF-APPSw,Ind)

Observed
  1. X
    Plaques at 22

    At 5-7 months of age diffuse amyloid-β plaques deposit in the dentate gyrus and neocortex. Amyloid deposition is progressive with widespread plaques by 8-10 months. Aβ puncta are deposited in the hippocampus as early as 1 month (Hong et al., 2016).

  2. X
    Neuronal Loss at 12

    Cell loss varies by brain region. No significant neuronal loss was observed in the CA3 region of the hippocampus at 6, 12, 24 and 36 weeks of age nor in the CA1 region at 6 weeks; however, at 12, 24, and 36 weeks significant neuronal loss was observed in the CA1 region compared to age-matched wild-type animals (Wright et al., 2013).

  3. X
    Gliosis at 24

    At 24 and 36 weeks a significant increase in the number of reactive GFAP+ astrocytes and CD68+ microglia was observed in the hippocampi of J20 mice compared to age-matched wild-type controls. No significant difference was observed at 6 and 12 weeks (Wright et al., 2013).

  4. X
    Synaptic Loss at 15

    Age-dependent loss of synaptophysin, synaptotagmin, PSD-95, and homer immunoreactivity in the hippocampus by 3 months; synapse loss was confirmed by electron microscopy. No significant difference was seen at 1 month (Hong et al., 2016).

  5. X
    Changes in LTP/LTD at 13

    Basal synaptic transmission is impaired between 3-6 months; extracellularly recorded field EPSPs at the Schaffer collateral to CA1 synapse in acute hippocampal slices were on average smaller in amplitude than those seen in wild-type mice. Significant deficits in LTP at the Schaffer collateral–CA1 synapse compared with control mice at 3-6 months (Saganich et al., 2006).

  6. X
    Cognitive Impairment at 16

    Deficits in spatial memory and learning appear as the mice age. By 4 months, J20 mice demonstrate spatial reference memory deficits as measured by the radial arm maze (Wright et al., 2013) and Morris water maze (Cheng et al., 2007).

Absent
  • Tangles at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish), APP V717F (Indiana) APP: Transgenic Alzheimer's Disease

Age-dependent formation of Aβ plaques. Dystrophic neurites associated with plaques. No tangles. Variable cell loss. Decrease in synaptic markers and increase in complement immunoreactvity.

Learning and memory deficits are age-dependent and may appear as early as 16 weeks. Hyperactivity and increased time in the open arm of the elevated plus maze than wild-type mice indicating lower levels of anxiety, but has not been universally replicated.

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JNPL3(P301L)

Observed
  1. X
    Tangles at 20

    Neurofibrillary tangles develop in an age and gene-dose dependent manner; as early as 4.5 months in homozygotes and 6.5 months in heterozygotes. Tangles and Pick-body-like neuronal inclusions in the amygdala, septal nuclei, preoptic nuclei, hypothalamus, midbrain, pons, medulla, deep cerebellar nuclei and spinal cord (Lewis et al., 2000).

  2. X
    Neuronal Loss at 43

    Neuronal loss, especially in the spinal cord, most prominent in the anterior horn (Lewis et al., 2000).

  3. X
    Gliosis at 43

    Astrogliosis (as measured by GFAP reactivity) in brainstem, diencephalon, and basal telencephalon by 10 months (Lewis et al., 2000).

Absent
  • Plaques at

    Absent.

No Data
  • Cognitive Impairment at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT P301L MAPT: Transgenic Frontotemporal Dementia, Progressive Supranuclear Palsy, Alzheimer's Disease

Age and gene-dose dependent development of neurofibrillary tangles as early as 4.5 months in homozygotes and 6.5 months in heterozyotes. Tangles and Pick-body-like inclusions in the amygdala, hypothalamus, pons, medulla, and spinal cord among other areas. Neuronal loss, especially in the spinal cord.

By 10 months, 90% developed motor and behavioral disturbances including limb weakness, hunched posture, decrease in grooming and vocalization.

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Kif21b*T82T/APOE4/Trem2*R47H

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Kif21b, APOE, Trem2 TREM2 R47H Kif21b: Knock-In; APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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MAPT 10IVS+16 C&gt;T

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT, MAPT-AS1, Mapt MAPT IVS10+16 C>T MAPT: Knock-In; MAPT-AS1: Knock-In; Mapt: Knock-Out Frontotemporal Dementia

Unknown.

Unknown.

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MAPT(H1.0)-GR

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT, MAPT-AS1, Mapt MAPT: Knock-In; MAPT-AS1: Knock-In; Mapt: Knock-Out Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy

Unknown.

Unknown.

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MAPT(H1.0*N279K)-GR

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT, MAPT-AS1, Mapt MAPT N279K MAPT: Knock-In; MAPT-AS1: Knock-In; Mapt: Knock-Out Frontotemporal Dementia

Unknown.

Unknown.

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MAPT(H1.0*)P301L-GR

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT, MAPT-AS1, Mapt MAPT P301L MAPT: Knock-In; MAPT-AS1: Knock-In; Mapt: Knock-Out Frontotemporal Dementia

Unknown.

No overt behavioral phenotypes

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MAPT(H2.1)-GR

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT, MAPT-AS1, Mapt MAPT: Knock-In; MAPT-AS1: Knock-In; Mapt: Knock-Out Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy

Unknown.

Unknown.

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MAPT knock-in

Observed
Absent
  • Plaques at

    No amyloid plaques at 24 months of age.

  • Tangles at

    No neurofibrillary tangles at 24 months of age.

  • Neuronal Loss at

    Neurodegeneration not apparent up to 2 years of age.

  • Gliosis at

    No astrogliosis or microgliosis observed at 24 months.

  • Cognitive Impairment at

    At 12 months of age, MAPT knock-in mice perform similarly to wild-type mice in the Y-maze test of working memory (only males tested).

No Data
  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT: Knock-In Alzheimer's Disease, Other Tauopathy

No evidence of increased neuroinflammation, neuronal death, or brain atrophy in MAPT knock-in mice, compared with wild-type mice.

MAPT knock-in mice perform similarly to wild-type mice in the Y-maze test of working memory.

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McGill-R-Thy1-APP

Observed
  1. X
    Plaques at 24

    Amyloid plaques present in homozygotes, appearing in hippocampus at 6 months and cortex at 13 months. Plaques are generally absent in hemizygotes.

  2. X
    Neuronal Loss at 72

    A 22 percent reduction in the number of neurons was seen in the subiculum of homozygous transgenic rats at 18 months.

  3. X
    Gliosis at 24

    Microgliosis and astrogliosis observed in homozyogotes.

  4. X
    Synaptic Loss at 80

    Reduction in cholinergic synaptic boutons seen at 20 months in homozygous transgenic rats.

  5. X
    Changes in LTP/LTD at 14

    Impairments in long-term potentiation in CA1 by 3.5 months of age.

  6. X
    Cognitive Impairment at 12

    Deficits in Morris water maze and fear conditioning test are apparent by 3 months of age in both hemizygous and homozygous transgenic rats.

Absent
No Data
  • Tangles at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish), APP V717F (Indiana) APP: Transgenic Alzheimer's Disease

Hemizygotes: intraneuronal Aβ in hippocampus and cortex by one week, but no plaques even at advanced ages. Homozygotes: intraneuronal Aβ in hippocampus and cortex by one week; amyloid plaques in hippocampus beginning at 6 months, in cortex beginning at 13 months.

Cognitive deficits are apparent by three months of age in both hemizygous and homozygous transgenic rats.

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Mthfr*C677T/APOE4/Trem2*R47H

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Mthfr, APOE, Trem2 TREM2 R47H Mthfr: Knock-In; APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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mThy-1 3R Tau (line 13)

Observed
  1. X
    Tangles at 34

    Pick-body like inclusions of aggregated tau appeared in the hippocampus and cortex by 8-10 months. Inclusions were positive for Bielchowsky silver stain but negative for Gallyas-silver stain and Thioflavin-S.

  2. X
    Neuronal Loss at 34

    Neuronal loss occurred by 8-10 months as evidenced by decreased NeuN staining in the dentate gyrus and CA3 regions of the hippocampus. Neocortical volume also decreased.

  3. X
    Gliosis at 35

    Astrogliosis was seen by 8-10 months in the neocortex and hippocampus. Some GFAP+ astrocytes also contained 3R tau.

  4. X
    Cognitive Impairment at 26

    By 6-8 months memory impairment was evident as a failure to habituate to a novel environment. This deficit was not present at 3-4 months. At 8-10 months, transgenics also took longer than wild-type mice to find the hidden platform in the Morris water maze.

Absent
  • Plaques at

    Absent.

No Data
  • Synaptic Loss at

    Synapto-dendritic damage manifested as reduced dendritic density, reduced MAP2 immunoreactivity, and accumulation of 3R tau in dendrites.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT L266V, MAPT G272V MAPT: Transgenic Frontotemporal Dementia, Pick's disease, Alzheimer's Disease

Accumulation of 3R tau in neurons of the cortex and hippocampus. Pick body-like tau aggregates and neuronal loss in the hippocampus and cortex. Astrogliosis, with some 3R tau in GFAP-positive astrocytes. Synapto-dendritic changes and mitochondrial pathology.

Age-related memory and motor deficits as assessed by habituation to a novel environment, the Morris water maze, and the round beam test.

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mThy1-hAPP751 (TASD41)

Observed
  1. X
    Plaques at 13

    Plaques start at 3-6 months in the frontal cortex and become widespread with age, affecting the piriform and olfactory cortices, hippocampus, and thalamus (Rockenstein et al., 2001; Havas et al., 2011).

  2. X
    Gliosis at 27

    Inflammation related to activated microglia (increased CD11) and reactive astrocytes (increased GFAP) is significant by 6 months and increases with age.

  3. X
    Synaptic Loss at 52

    Dystrophic neurites and synaptic loss starting at 12 months.

  4. X
    Cognitive Impairment at 26

    Cognitive impairment observed by 6 months by Morris Water Maze (Rockenstein et al., 2005).

Absent
  • Tangles at

    Absent.

  • Neuronal Loss at

    Absent.

No Data
  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish), APP V717I (London) APP: Transgenic Alzheimer's Disease

Age-dependent increases in Aβ40 and Aβ42, with Aβ42 > Aβ40. Plaques at an early age, starting at 3-6 months in the frontal cortex. At 5-7 months, size and number of plaques increased in the frontal cortex, and dense amyloid deposits appear in hippocampous, thalamus, and olfactory region.

Age-associated impairment in spatial memory and learning in the water maze task and habituation in the hole-board task, with significant deficits at 6 months of age. Some gender-specific differences in open field exploration.

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NSE-APP751

Observed
  1. X
    Plaques at 8

    Aβ deposits were observed as early as two months of age. These deposits were diffuse and extracellular and had a “cotton-like” appearance. Classic mature plaques were not observed.

  2. X
    Gliosis at 95

    Gliosis was noted in a single 22-month-old animal with extensive Aβ deposits (Higgins et al., 1994).

  3. X
    Cognitive Impairment at 52

    Deficits in spatial memory and learning appear as the mice age. At 12 months the mice demonstrate learning and memory deficits as measured by a water-maze task and in spontaneous alternation in a Y maze (Moran et al., 1995). At six months cognition is largely normal.

Absent
  • Tangles at

    Classic tangles were not observed, but aberrant tau immunoreactivity was observed as early as two months.

  • Neuronal Loss at

    Cell death was not formally assessed, however, overt neuronal death was not seen.

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP: Transgenic Alzheimer's Disease

Age-dependent increase in Aβ deposits and tau immunoreactivity.

Learning and memory deficits are age-dependent as assessed on spontaneous alternation in a Y maze and in the water-maze task.

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PA-Rab5

Observed
  1. X
    Neuronal Loss at 28

    Loss of basal forebrain cholinergic neurons, beginning at 7 months.

  2. X
    Synaptic Loss at 34

    Loss of spines in CA3 and dentate gyrus regions of the hippocampus, observed in 8.5-month-old mice.

  3. X
    Changes in LTP/LTD at 24

    Pronounced defect in LTD and slight impairment in LTD at Schaffer collateral-CA1 synapses in hippocampal slices from 6-month-old mice.

  4. X
    Cognitive Impairment at 24

    When tested at 6 months of age, the performance of PA-Rab5 mice differed from wild-type controls in a novel object recognition test.

Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Gliosis at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
RAB5A RAB5A: Transgenic Alzheimer's Disease

Enlarged Rab5-positive endosomes, tau hyperphosphorylation, synapse loss in hippocampus, and loss of basal forebrain cholinergic neurons.

When tested at 6 months of age, the performance of PA-Rab5 mice differed from wild-type controls in a novel object recognition test.

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PDAPP(line109)

Observed
  1. X
    Plaques at 26

    In heterozygous mice no plaque pathology at 4-6 months. At 6-9 months mice begin to exhibit deposits of human Aβ in the hippocampus, corpus callosum, and cerebral cortex. Plaques become more extensive with age and vary in size and structure including diffuse irregular plaques and compact cored plaques (Games et al., 1995).

  2. X
    Gliosis at 26

    GFAP-positive astrocytes and activated microglia associated with plaques (Games et al., 1995).

  3. X
    Synaptic Loss at 35

    Decreased synaptic density in the dentate gyrus as measured by synaptophysin immunoreactivity. Also decreased dendritic density as measured by MAP2 immunoreactivity (Games et al., 1995).

  4. X
    Changes in LTP/LTD at 17

    Alterations in LTP induced by theta burst stimulation at 4-5 months which is prior to plaque formation; although the potentiation immediately after TBS was comparable to control mice, the potentiation decayed more rapidly in PDAPP mice. Also paired pulse facilitation was enhanced. Responses to high frequency stimulation bursts were distorted (Larson et al., 1999).

  5. X
    Cognitive Impairment at 13

    Deficits in a variety of memory paradigms from a young age. Robust deficits in the radial arm maze at 3 months (deficits appear before amyloid plaque deposits). Object recognition, 6, 9-10 months. Operant learning, 3, 6 months (Dodart et al., 1999).

Absent
  • Tangles at

    No paired helical filaments or aggregates, but phosphorylated tau immunoreactivity is observed in dystrophic neurites after 14 months (Masliah et al., 2001).

  • Neuronal Loss at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP V717F (Indiana) APP: Transgenic Alzheimer's Disease

Amyloid plaques in the hippocampus, cerebral cortex. Gliosis. Dystrophic neurites. Decreased synaptic and dendritic density in the hippocampus.

Deficits in a variety of memory paradigms from a young age. Deficits in the radial arm maze at 3 months (before plaques), object recognition, operant learning, spatial reference memory (starting at 3-4 months), cued fear conditioning at 11 months.

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PDGF-APP(WT) (line I5)

Observed
  1. X
    Synaptic Loss at 9

    By 2-4 months of age, there is a decrease in synaptophysin-immunoreactive presynaptic terminals compared to nonTg controls. Synaptophysin immunoreactivity decreases further with age.

Absent
  • Tangles at

    Not observed.

  • Neuronal Loss at

    Not observed.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP: Transgenic Alzheimer's Disease

Expression of human APP in the brain especially in the neocortex and hippocampus. No plaques up to 24 months.

Unknown.

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PLB1-triple (hAPP/hTau/hPS1)

Observed
  1. X
    Gliosis at 52

    Increased inflammation (GFAP labelling) detected at 12 months in cortex and hippocampus (Platt, unpublished observation).

  2. X
    Changes in LTP/LTD at 26

    Impairments in long-term and short-term hippocampal plasticity. LTP following theta-burst stimulation decayed faster and paired-pulse facilitation was reduced relative to wild-type mice at both six and 12 months of age. Synaptic transmission impacted at 12 months.

  3. X
    Cognitive Impairment at 22

    Social recognition memory was impaired by five months and further impaired by 12 months. Similarly, object recognition memory was impaired by eight months. Spatial learning impairments were seen later; at 12 months deficits in spatial acquisition learning were seen in the open field water maze that were not apparent at 5 months.

Absent
  • Plaques at

    Sparse plaques out to 21 months of age. Only marginally increased compared with wild-types and overall very low compared to over-expression models. However, Aβ accumulated intracellularly and also formed oligomers.

  • Tangles at

    No overt tangle pathology; however, hyyperphosphorylated tau accumulated in the hippocampus and cortex from six months of age.

  • Neuronal Loss at

    Absent.

No Data
  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, MAPT, PSEN1 APP V717I (London), APP K670_M671delinsNL (Swedish), PSEN1 A246E, MAPT P301L, MAPT R406W APP: Multi-transgene; MAPT: Multi-transgene; PSEN1: Multi-transgene Alzheimer's Disease

Age-related neuropathology including intraneuronal and oligomeric Aβ accumulation and hyperphosphorylated tau in the hippocampus and cortex from six months. Minimal amyloid plaques up to 21 months. Subtle tau pathology, but no overt tangles. Cortical hypometabolism with increased metabolic activity in basal forebrain and ventral midbrain by FDG-PET/CT.

Cognitive deficits in recognition memory and spatial learning emerging between five and 12 months. Impairments in hippocampal plasticity.

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PLB4 (hBACE1)

Observed
  1. X
    Gliosis at 52

    Increased GFAP-positive astrocytes at 12 months of age in the dentate gyrus, CA1 region of the hippocampus, and the piriform cortex. Gliosis is suspected to begin earlier than 12 months.

  2. X
    Cognitive Impairment at 13

    Impaired spatial representation in a habituation task by 3 months of age. By 6 months, impaired learning and memory by a variety of tasks including the Y-maze, Morris water maze, and a test of the social transmission of food preference. These effects appear to be distinct from reduced motor activity and reduced anxiety.

Absent
  • Plaques at

    Plaques virtually absent, minimal small sparse plaques. However, prominent extracellular Aβ staining surrounding neuronal cell bodies, including Aβ multimers (e.g. Aβ*56 and Aβ hexamers).

  • Tangles at

    Preliminary analysis did not find abnormal phosphorylation or conformational changes in tau.

No Data
  • Neuronal Loss at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
BACE1 BACE1: Transgenic Alzheimer's Disease

Elevated extracellular multimeric Aβ, including Aβ*56 and Aβ hexamers, in the absence of plaques. At 12 months of age, astrogliosis was observed in a region- and genotype-dependent manner, especially in the dentate gyrus, hippocampal CA1, and piriform cortex. No overt tau pathology.

Largely intact motor coordination and gait (Rotarod, CatWalk). Age-associated changes in multiple measures of learning and memory. Early deficits in habituation to a novel environment and semantic-like memory (three-four months). Impaired spatial learning and long-term reference (Morris water maze) and working memory (Y-maze) at six months, distinct from reduced locomotor activity and anxiety.

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Plcγ2-P522R knock-in

Observed
  1. X
    Gliosis at 24

    Astrogliosis revealed by GFAP immunohistochemistry in 6-month-old males. Microglial activation revealed by TSPO PET imaging in year-old females.

Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Plcg2 Plcg2: Knock-In Alzheimer's Disease, Dementia with Lewy Bodies, Frontotemporal Dementia

Hypertrophic astrocytes in the hippocampi, revealed by GFAP immunohistochemistry. Microglial activation revealed by TSPO PET imaging.

Unknown.

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Plcg2 KO

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Plcg2 Plcg2: Knock-Out Alzheimer's Disease

Unknown.

Unknown.

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Plcg2*M28L/APOE4/Trem2*R47H

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE, Plcg2, Trem2 TREM2 R47H APOE: Knock-In; Plcg2: Knock-In; Trem2: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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Plcg2*M28L x 5xFAD

Observed
  1. X
    Plaques at 30

    Diffuse and compact amyloid plaques observed in mice studied at 7.5 months of age. Higher plaque burdens than 5xFAD.

  2. X
    Gliosis at 31

    Microgliosis observed in mice studied at 7.5 months of age.

  3. X
    Synaptic Loss at 32

    Decreased basal synaptic transmission, lower frequencies and amplitudes of spontaneous excitatory postsynaptic currents and spontaneous inhibitory postsynaptic currents recorded in hippocampal CA1 region, compared with wild-type mice.

  4. X
    Changes in LTP/LTD at 33

    Impaired LTP at Schaffer collateral-CA1 synapses, compared with wild-type.

  5. X
    Cognitive Impairment at 24

    Deficits in working memory (decreased spontaneous alternation in the Y-maze), compared with wild-type.

Absent
No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Plcg2, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V Plcg2: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Plaque burdens in the cortex and subiculum were elevated in 5xFADM28L mice but microglia showed less interaction with plaques, compared with 5xFAD.

Six-month-old 5xFADM28L and 5xFAD mice showed similar deficits in working memory, assessed in the Y-maze.

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Plcg2*P522R

Observed
  1. X
    Gliosis at 24

    Plcg2*P522R knock-in mice had a slightly higher density of Iba1-positive microglia than wild-type mice. Microglia in the knock-in animals were simpler in shape—with less ramified processes—and contained a greater density of puncta immunoreactive for the lysosomal marker CD68, compared with wild-type microglia.

Absent
  • Synaptic Loss at

    Synapse number in hippocampal CA1—assessed as the density of puncta immunoreactive for the presynaptic marker bassoon or the postsynaptic marker PSD95—did not differ between Plcg2*P522R and wild-type mice. However, a slight decrease in the number of thin spines was observed in mutation carriers, while numbers of stubby and mushroom spines did not differ between the genotypes.

No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Plcg2 Plcg2: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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Plcg2*P522R x 5xFAD

Observed
  1. X
    Plaques at 30

    Diffuse and compact amyloid plaques observed in mice studied at 7.5 months of age. Lower plaque burdens than 5xFAD.

  2. X
    Gliosis at 31

    Microgliosis observed in mice studied at 7.5 months of age.

Absent
  • Synaptic Loss at

    No deficits in synaptic transmission—including basal synaptic transmission, frequencies and amplitudes of spontaneous excitatory postsynaptic currents and spontaneous inhibitory postsynaptic currents, and AMPA/NMDA current ratios—recorded in hippocampal CA1 region of 7.5-month-old mice.

  • Changes in LTP/LTD at

    Normal LTP at Schaffer collateral-CA1 synapses at 7.5 months of age.

  • Cognitive Impairment at

    Normal working memory (spontaneous alternation in the Y-maze) at 6 months of age.

No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Plcg2, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V Plcg2: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Plaque burdens in the cortex and subiculum were lower in 5xFADP522R mice and microglia showed increased interaction with plaques, compared with 5xFAD.

The PLCγ2 P522R variant protected against deficits in the Y-maze test of working memory in 5xFAD mice.

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Plcg2*P522R x APP NL-G-F

Observed
  1. X
    Plaques at 24

    ThioflavinS-positive amyloid plaques observed in mice studied at 6 months of age. Higher plaque burdens than APPNL-G-F.

  2. X
    Gliosis at 24

    Microgliosis observed in mice studied at 6 months of age. Attenuated microglia-plaque interactions in the hippocampus, compared with APPNL-G-F.

Absent
  • Synaptic Loss at

    The P522R variant attenuated the synapse loss observed in APPNL-G-F mice with wild-type PLCγ2.

No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Plcg2, App APP K670_M671delinsNL (Swedish), APP I716F (Iberian), APP E693G (Arctic) Plcg2: Knock-In; App: Knock-In Alzheimer's Disease

Sex- and region-dependent increases in plaque burden, and decreases in microglia-plaque interactions, in Plcg2*P552R x APPNL-G-F mice, compared with APPNL-G-F.

Unknown.

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PS19 with humanized TREM2 (common variant)

Observed
  1. X
    Tangles at 37

    Tangles revealed using antibody PG5 at 9 months.

  2. X
    Neuronal Loss at 38

    At 9 months, atrophy of hippocampus and entorhinal/piriform cortex and pronounced ventricular expansion. Thinning of the granule cell layer of the dentate gyrus and pyramidal cell layer of the piriform cortex, compared with PS19 mice carrying TREM2-R47H.

  3. X
    Gliosis at 39

    Elevated expression of markers of astroglial and microglial reactivity, compared with PS19 mice carrying the R47H variant of TREM2.

  4. X
    Synaptic Loss at 40

    Fewer synapses and more dystrophic synapses, compared with PS19 mice carrying the R47H variant of TREM2.

Absent
No Data
  • Plaques at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT, TREM2, Trem2 MAPT P301S MAPT: Transgenic; TREM2: Transgenic; Trem2: Knock-Out Alzheimer's Disease, Frontotemporal Dementia

Brain atrophy by 9 months of age. Increased microgliosis, astrogliosis and synapse loss, compared with PS19 mice carrying TREM2 with the R47H mutation.

Not known.

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PS19 with humanized TREM2 (R47H)

Observed
  1. X
    Tangles at 36

    Tangles revealed using antibody PG5 at 9 months.

Absent
No Data
  • Plaques at

    No data.

  • Neuronal Loss at

    No data relative to wild-type mice, but at 9 months of age, the volumes of the hippocampus and entorhinal/piriform cortex are larger, and the granule cell layer of the dentate gyrus and pyramidal cell layer of the piriform cortex are thicker, in PS19-TREM2R47H mice, compared with PS19 mice carrying the common variant of human TREM2.

  • Gliosis at

    At 9 months of age, decreased expression of markers of astroglial and microglial reactivity, compared with PS19 mice carrying the common variant of TREM2, but no data relative to wild-type mice.

  • Synaptic Loss at

    At 9 months of age, more synapses and fewer dystrophic synapses, compared with PS19 mice carrying the common variant of TREM2, but no data relative to wild-type mice.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT, TREM2, Trem2 MAPT P301S, TREM2 R47H MAPT: Transgenic; TREM2: Transgenic; Trem2: Knock-Out Alzheimer's Disease, Frontotemporal Dementia

Decreased brain atrophy, microgliosis, astrogliosis, and synapse loss, compared with PS19 mice carrying the common variant of TREM2.

Not known.

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PS1 conditional Knock-out

Observed
  1. X
    Cognitive Impairment at 22

    Mild impairment of spatial learning and memory in the Morris water maze observed in 5 month-old mice (Yu et al., 2001).

Absent
  • Plaques at

    Absent.

  • Tangles at

    Absent.

  • Neuronal Loss at

    Absent.

  • Changes in LTP/LTD at

    Mice at 3-6 months of age exhibit normal paired-pulse facilitation, LTP, and LTD in the Schaffer collateral pathway of the hippocampus (Yu et al., 2001).

No Data
  • Gliosis at

    Unknown.

  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
PSEN1 PSEN1: Conditional Knock-out Alzheimer's Disease

Reduction in Aβ40 and Aβ42 peptides; accumulation of APP C-terminal fragments.

Subtle but significant deficits in long-term spatial memory in the Morris water maze.

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PS2APP

Observed
  1. X
    Plaques at 26

    Age-associated development of plaques: none at 3 months, overt Aβ deposition at approximately 6 months, with heavy plaque load in the hippocampus, frontal cortex, and subiculum at 10 months (Ozmen et al., 2009; Weidensteiner et al. 2009).

  2. X
    Gliosis at 26

    Gliosis at 6 months (personal communication, Laurence Ozmen).

  3. X
    Changes in LTP/LTD at 43

    A strong increase in LTP and post-tetanic potentiation induced by tetanic stimulation in hippocampal slices of 10 month-old animals compared to wild-type mice (Poirier et al., 2010).

  4. X
    Cognitive Impairment at 35

    Cognitive impairment is detected by the Morris water maze (probe trial 2) at 8 and 12 months of age, not at 3 months (personal communication Laurence Ozmen).

Absent
  • Tangles at

    Absent.

No Data
  • Neuronal Loss at

    Unknown.

  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN2 APP K670_M671delinsNL (Swedish), PSEN2 N141I APP: Transgenic; PSEN2: Transgenic Alzheimer's Disease

Age-associated development of plaques: none at 3 months, overt Aβ deposition in the brain at approximately 6 months, with heavy plaque load in the hippocampus, frontal cortex, and subiculum at 10 months. Aβ deposits in blood vessels were sporadic, mainly in large vessels. Cerebral amyloid deposits correlate with levels of the human APP transcript at 12 months.

Cognitive impariment detected by the Morris water maze at 8 and 12 months of age, but not at 3 months.

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PS2APP (PS2(N141I) x APPswe)

Observed
  1. X
    Plaques at 39

    Rare amyloid deposits at 5 months, with consistent deposits in the subiculum and frontolateral cortices by 9 months. Plaques increase in number and distribution over time, spreading throughout the neocortex and hippocampus as well as the amygdala and thalamic and pontine nuclei (Richards et al., 2003).

  2. X
    Gliosis at 39

    An inflammatory response indicated by the presence of activated microglia and astrocytes begins around 9 months. The onset, distribution, and abundance of activated microglia and astrocytes correlate with Aβ deposition.

  3. X
    Cognitive Impairment at 35

    Age-associated cognitive impairment from 8 months with impaired acquisition of spatial learning in the water maze (Richards et al., 2003).

Absent
  • Tangles at

    Absent.

  • Changes in LTP/LTD at

    No difference in LTP in the dentate gyrus at 3 and 10 months compared to wild-type mice (Richards et al., 2003).

No Data
  • Neuronal Loss at

    Unknown.

  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN2 APP K670_M671delinsNL (Swedish), PSEN2 N141I APP: Transgenic; PSEN2: Transgenic Alzheimer's Disease

Rare amyloid deposits at 5 months, with consistent deposits in the subiculum and frontolateral cortices by 9 months. Plaques increase in number and distribution with time, spreading throughout the neocortex and hippocampus as well as the amygdala and thalamic and pontine nuclei. The distribution and abundance of activated microglia and astrocytes correlate with Aβ deposition.

Mice develop age-associated cognitive impairment from 8 months with impaired acquisition of spatial learning in the water maze.

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PS/APP

Observed
  1. X
    Plaques at 26

    Large amounts of Aβ accumulate in the cerebral cortex and hippocampus, starting around 6 months and increasing with age. Other brain regions are affected later. Both diffuse and fibrillar plaques form (Gordon et al., 2002).

  2. X
    Neuronal Loss at 79

    Neuronal loss in the CA1 region of the hippocampus has been reported at 22 months accompanied by reduced glucose utilization (Sadowski et al., 2004).

  3. X
    Gliosis at 26

    GFAP-positive astrocytes appear first in the cortex in the vicinity of the developing Aβ deposits. Numbers increase with age, becoming confluent. Numbers of resting microglia (positive for complement receptor-3) increase in the vicinity of deposits at 6 months, but activated microglia (positive for MHC-II) are negligible before 12 months and more variable (Gordon et al., 2002).

  4. X
    Cognitive Impairment at 12

    Double and single transgenic mice had reduced spontaneous alternation performance in a “Y” maze, a test of spatial memory, at 12-14 weeks, before substantial Aβ deposition (Holcomb et al., 1998). Progressive age-related cognitive impairment is seen later in select tasks (e.g. water maze acquisition and radial arm water maze working memory)(Arendash et al., 2001).

Absent
  • Tangles at

    Neurofibrillary tangles are not associated with this model, but hyperphosphorylated tau is detected, starting at 24 weeks, appearing as punctate deposits near amyloid deposits in the cortex and hippocampus (Kurt et al., 2003).

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1 M146L (A>C) APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Aβ accumulates in the cerebral cortex and hippocampus starting ~6 months and increasing with age. Other regions affected later. Deposition occurs in white matter,  cerebrovasculature, and grey matter in the form of diffuse and fibrillar plaques. Fibrillar deposits are associated with dystrophic neurites and GFAP-positive astrocytes at ~ 6 months with later microglial activation.

Progressive impairment between 5–7 and 15–17 months in some tests of cognitive performance, but not others. No change in anxiety levels.

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PS cDKO

Observed
  1. X
    Neuronal Loss at 9

    Significant increase (about 8-fold) in apoptotic neurons at 2 months of age, although the total number of cortical neurons is not significantly altered due to the low basal level of apoptosis in the cerebral cortex. By 4 months of age, the cumulative loss of cortical neurons reaches about 9 percent of all cortical neurons.

  2. X
    Gliosis at 17

    Astrogliosis and microgliosis; up-regulation of GFAP and other inflammatory markers are observed in the neocortex and hippocampus at 6 months, and this increases with age (Wines-Samuelson et al., 2010, Beglopoulos et al., 2004). 

  3. X
    Synaptic Loss at 26

    Reduction in synaptophysin immunoreactivity in hippocampal CA1 pyramidal neurons by 6 months. Reduction in dendritic spines by 9 months (Saura et al., 2004).

  4. X
    Cognitive Impairment at 9

    Deficits in the Morris water maze and contextual fear conditioning are mild at 2 months, but become more severe with age (Saura et al., 2004). 

Absent
  • Plaques at

    Absent.

  • Tangles at

    Tangles are absent, but hyperphosphorylation of tau has been reported in 9 month-old mice.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
PSEN1, PSEN2 PSEN1: Conditional Knock-out; PSEN2: Knock-Out Alzheimer's Disease

At 2 months the number of apoptotic neurons is elevated about 8-fold. By 6 months, about 18 percent of of cortical neurons are lost. Up-regulation of inflammatory markers and progressive astrogliosis and microgliosis in the neocortex and hippocampus.

Impairments in hippocampal learning and memory as indicated by Morris water maze and contextual fear conditioning evident by 2 months and worsens with age.

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Psen1 L435F knock-in

Observed
Absent
  • Plaques at

    No plaques at 15 days of age.

  • Neuronal Loss at

    No neuron loss at 15 days of age.

  • Gliosis at

    No astrogliosis or microgliosis at 15 days of age.

No Data
  • Tangles at

    No data. 

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Psen1, App PSEN1 L435F Psen1: Knock-In; App: Knock-In Alzheimer's Disease

None observed in 15-day-old rats.

Unknown.

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PWK.APP/PS1

Observed
  1. X
    Plaques at 32

    Thioflavin S-positive amyloid plaques are present in the cortex and CA1 region of the hippocampus by 8 months of age, with females having more plaques in the cortex than males.

  2. X
    Gliosis at 33

    Plaque-associated microgliosis observed by 8 months.

Absent
  • Tangles at

    Not observed.

  • Neuronal Loss at

    Not observed.

  • Cognitive Impairment at

    Working memory and short-term memory were intact at 7 to 8 months, as assessed by tests in the Y-maze.

No Data
  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques and plaque-associated gliosis by 8 months.

Transgenic mice are hyperactive and aggressive. Working memory and short-term memory are intact at 7 to 8 months, as assessed by tests in the Y-maze.

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rTg9191

Observed
  1. X
    Plaques at 35

    Plaques emerge first in the cerebral cortex, starting around 8 months of age. This is followed by plaques in the hippocampus at 10.5 to 12.5 months of age. Some dense core plaques develop.

  2. X
    Neuronal Loss at 9

    Expression of the tetracycline transactivator (tTA) resulted in reduced forebrain weight and smaller dentate gyri in rTg9191 mice compared to non-Tg littermates. This effect was also observed in mice expressing tTA alone, and is thought to be a developmental effect, as it was observed even in young mice (e.g., 2-6 months of age).

  3. X
    Gliosis at 104

    rTg9191 mice develop reactive gliosis (astrocytosis and microgliosis) in the vicinity of dense-core plaques by 24 months of age.

Absent
  • Tangles at

    Tangles are not observed, but hyperphosphorylated tau develops with age.

  • Cognitive Impairment at

    No transgene-related deficits seen in Morris water maze (4, 12, 21, 24 months of age) or fixed consecutive number test (23 months of age).

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish), APP V717I (London) APP: Transgenic Alzheimer's Disease

Age-associated pathology in the cerebral cortex and hippocampus starting at 8 and 10½-12½ months of age, respectively. Gliosis and hyperphosphorylated tau in the vicinity of dense-core plaques. Fibrillar oligomeric species, e.g., Aβ dimers.

No transgene-related deficits seen in Morris water maze (4, 12, 21, 24, months of age) or fixed consecutive-number (23 months of age) tests.

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rTgTauEC

Observed
  1. X
    Tangles at 78

    By 18 months of age, Gallyas silver-positive staining is observed, indicative of paired helical filaments. This is followed by thioflavin-S staining at 24 months. Tau pathology develops first in neurons of the medial EC expressing human tau, followed by neurons in the dentate gyrus, CA1 and CA2/3(de Calignon et al., 2012).

  2. X
    Neuronal Loss at 83

    Neuronal loss is detectable by 24 months of age in areas with transgene expression (e.g. layer II of the EC and parasubiculum), compared with age-matched mice expressing only tTA. Significant neuronal loss was not observed at 21 months (de Calignon et al., 2012).

  3. X
    Gliosis at 104

    Microglial activation and astrogliosis by 24 months of age, in conjunction with axonal degeneration and neuronal loss (de Calignon et al., 2012).

  4. X
    Synaptic Loss at 104

    By 24 months of age pre- and post-synaptic densities were reduced in the middle third of the molecular layer of the dentate gyrus as measured by synapsin-1 and PSD-95 staining (de Calignon et al., 2012).

  5. X
    Changes in LTP/LTD at 70

    At 16 months of age, subtle differences in electrophysiological properties have been observed in the perforant pathway, including a decrease in LTP and an increase in the probability of neurotransmitter release (Polydoro et al., 2014).

  6. X
    Cognitive Impairment at 70

    Very mild and specific deficits in contextual fear conditioning at 16 months of age, but no deficits in the radial arm maze (Polydoro et al., 2014).

Absent
  • Plaques at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT P301L MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease

Propagating tau pathology starting in the entorhinal cortex and spreading to regions functionally connected to the EC (e.g., dentate gyrus). Neurodegeneration and axonal degeneration, first in EC and parasubiculum. Gliosis and synaptic loss.

Subtle cognitive deficit in contextual fear conditioning, but not in the radial arm maze, at 16 months. Mild specific deficit in locomotor activity in the open field test.

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rTg(tauP301L)4510

Observed
  1. X
    Tangles at 17

    Pretangles as early as 2.5 months. Argyrophilic tangle-like inclusions in cortex by 4 months and in hippocampus by 5.5 months.

  2. X
    Neuronal Loss at 24

    Decreased (~60%) CA1 hippocampal neurons by 5.5 months with significant loss in brain weight. Progressive loss of neurons and brain weight in 7 and 8.5 month mice with ~23% of CA1 pyramidal cells remaining at 8.5 months. Gross atrophy of the forebrain by 10 months.

  3. X
    Synaptic Loss at 35

    Significant loss of dendritic spines at 8-9 months (~30% decrease in spine density in somatosensory cortex).

  4. X
    Cognitive Impairment at 11

    Retention of spatial memory (Morris Water Maze) became impaired from 2.5 to 4 months. No significant motor impairments up to 6 months. Spatial memory improved when transgene suppressed by dox.

Absent
  • Plaques at

    Absent.

No Data
  • Changes in LTP/LTD at

    LTP at the Schaffer collateral-CA1 synapse is normal at 1.3 months, but impaired at 4.5 months.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT P301L MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia

Argyrophilic tangle-like inclusions in cortex by 4 months and in hippocampus by 5.5 months. Decreased CA1 neurons (~60 percent) by 5.5 months. Gross forebrain atrophy by 10 months. The number of CA1 neurons stabilized after a brief (six to eight week) suppression of transgenic tau.

Spatial memory impairments by 2.5 to 4 months. No significant motor impairment up to 6 months of age. When the transgene was suppressed with dox at 2.5 months, spatial memory improved.

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SHR24

Observed
  1. X
    Tangles at 38

    Argyrophilic neurofibrillary tangles accumulate in cortex, hippocampus, thalamus, and brainstem.

  2. X
    Synaptic Loss at 60

    Decreased levels of synaptophysin and a decreased number of synaptic vesicles per synapse in animals at the end of the lifespan of this line.

Absent
  • Neuronal Loss at

    No neuron loss was observed in the hippocampi or cortices of male rats examined at 15 month of age.

No Data
  • Plaques at

    No data.

  • Gliosis at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    Sensorimotor deficits and abnormal reflexes observed as early as 3.5 months, but no data available from cognitive tests.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT: Transgenic Alzheimer's Disease

Neurofibrillary tangles accumulate in cortex, hippocampus, thalamus, and brainstem, beginning at 9 to 10 months. No neuron loss was observed in the hippocampus or cortex.

SHR24 rats exhibit age-dependent impairments in several neurobehavioral tests; hind-limb clasping during the tail-hang test is one of the earliest abnormalities to appear, evident by 3.5 months of age.

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SHR318

Observed
  1. X
    Tangles at 38

    Argyrophilic neurofibrillary tangles are particularly prominent in the brainstem and spinal cord.

  2. X
    Cognitive Impairment at 18

    At 4.5 months, rats show normal learning, but deficits in spatial memory, in the Morris water maze.

Absent
  • Neuronal Loss at

    Neuron numbers in the hippocampi and brainstem gigantocellular reticular nucleus do not differ between 10.5-month SHR318 rats and non-transgenic rats.

No Data
  • Plaques at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT: Transgenic Alzheimer's Disease

Neurofibrillary tangles first appear at 9 months and are particularly prominent in the brainstem and spinal cord. Axonal degeneration is observed in the brainstem and spinal cord of 10- to 12-month animals.

At 4.5 months, rats show normal learning, but deficits in spatial memory, in the Morris water maze. Reflexes and sensorimotor coordination are impaired at 7 months.

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SHR72

Observed
  1. X
    Tangles at 30

    Neurofibrillary tangles, demonstrated by Gallyas silver stain, are present in the brainstem and spinal cord.

  2. X
    Gliosis at 29

    Astrogliosis and microgliosis are present in brainstem regions bearing neurofibrillary tangles.

Absent
  • Neuronal Loss at

    Although neuron loss has not been documented, chromatolytic neurons and damaged axons were seen in the brains of 7-month animals, particularly in the brainstem reticular formation.

No Data
  • Plaques at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    Sensorimotor deficits and abnormal reflexes observed as early as 3 months, but no data available from cognitive tests.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT: Transgenic Alzheimer's Disease

Neurofibrillary tangles, demonstrated by Gallyas silver stain, were found the brainstems and spinal cords of terminal stage (7- to 8-month old) animals. Chromatolytic neurons and damaged axons were also observed at this stage.

Sensorimotor deficits and loss of muscle strength are apparent at 3 months. This stage lasted about three months, and then rats experienced a rapid, dramatic decline in neurological function, succumbing within several days.

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SHRSP/FAD

Observed
  1. X
    Plaques at 69

    Diffuse amyloid plaques observed at 16-18 months, the only age examined to date.

  2. X
    Tangles at 70

    Occasional neurons appear to contain globose neurofibrillary tangles, as revealed by immunostaining using an antibody directed against tau phosphorylated at serine 422, an epitope found in paired helical filaments.

  3. X
    Gliosis at 71

    Hypertrophied microglia and elevated levels of GFAP observed at 16-18 months, the only age examined to date.

  4. X
    Cognitive Impairment at 72

    Working memory deficits as assessed by novel object recognition, but not as assessed by spontaneous alternation in the Y-maze, at 16-18 months, the only age examined to date.

Absent
  • Synaptic Loss at

    Levels of SNAP25, synaptophysin, and drebrin do not differ from non-hypertensive, non-transgenic rats at 16-18 months, the only age examined to date.

No Data
  • Neuronal Loss at

    A reduction in calbindin staining might reflect a loss of inhibitory neurons. Levels of caspase-cleaved actin, a marker of apoptosis, are elevated, compared with non-hypertensive, non-transgenic rats.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease, Vascular Dementia

Amyloid plaques, microgliosis, and possible astrogliosis. Occasional neurons appear to contain paired helical filament tau. Demyelination. Reduced calbindin immunoreactivity and increased levels of caspase-cleaved actin may indicate neuron loss.

Hyperactive. Working memory deficits as assessed by novel object recognition, but not as assessed by spontaneous alternation in the Y-maze.

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Snx1*D465N/APOE4/Trem2*R47H

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Snx1, APOE, Trem2 TREM2 R47H Snx1: Knock-In; APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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Sorl1*A528T

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Sorl1 SORL1 A528T (SNP 13) Sorl1: Knock-In Alzheimer's Disease

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Sorl1*A528T/APOE4/Trem2*R47H

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Sorl1, APOE, Trem2 TREM2 R47H, SORL1 A528T (SNP 13), APOE C130R (ApoE4) Sorl1: Knock-In; APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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SORL1 transgenic (Cre-inducible)

Observed
Absent
  • Changes in LTP/LTD at

    LTP at Schaffer collateral-CA synapses was similar in hippocampal slices from 3-month-old Rosa26Tg/+ and wild-type mice. The application of Aβ oligomers impaired LTP in slices from wild-type mice but did not affect LTP in SORL1 transgenic mice.

  • Cognitive Impairment at

    Three-month-old Rosa26Tg/+ SORL1 transgenic mice performed similarly to wild-type mice in the acquisition and retention phases of the Morris Water Maze test. Hippocampal injection of Aβ oligomers prevented wild-type mice from learning the location of the escape platform but did not affect the performance of the transgenic mice.

No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
SORL1 SORL1: Transgenic Alzheimer's Disease

Unknown.

Normal performance in the Morris Water Maze.

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SORLA-deficient

Observed
Absent
  • Plaques at

    No amyloid plaques observed up to 10 months of age. When SORLA-deficient mice are crossed with APP transgenic models of amyloidosis, amyloid deposition is accelerated, compared with the parental APP transgenic line.

No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    Neuron loss was not seen in the substantia nigra and ventral tegmental areas, assessed at 5 weeks and 45 weeks. Data on neuron numbers are not available from other brain regions. Nigrostriatal connectivity appears to be disrupted in SORLA-deficient mice.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No differences in LTP were observed in hippocampal slices from 10- to 12-month-old Sorl1-/- mice and slices from littermates heterozygous for the Sorl1 deletion (Rohe et al., 2008). It is not known whether LTP in these genotypes differs from that of wild-type mice.

  • Cognitive Impairment at

    Compared with wild-type mice, SORLA-deficient mice exhibited more arm entries and more time spent in the open arms of the elevated plus maze—behaviors interpreted as evidence of hyperactivity and reduced anxiety. Hyperactivity was also noticed in the open field test.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Sorl1 Sorl1: Knock-Out Alzheimer's Disease

Mice do not generate amyloid plaques. Disrupted nigrostriatal connectivity and thinner inner nuclear layer of the retina.

Hyperactivity and reduced anxiety, compared with wild-type mice.

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TAS10 (thy1-APPswe)

Observed
  1. X
    Plaques at 52

    Fibrillar amyloid plaques develop by 12 months in the cortex and hippocampus.

  2. X
    Gliosis at 26

    Astrogliosis and microgliosis underway by 6 months of age in the dentate gyrus.

  3. X
    Synaptic Loss at 104

    TAS10 mice initially have more synapses than non-Tg mice; specifically, greater numbers of synapses per neuron were documented at 12 and 18 months of age. However, by 24 months of age, TAS10 mice have fewer synapses than non-Tg mice.

  4. X
    Cognitive Impairment at 26

    Deficits in spatial learning present by 6 months of age as measured by the Morris water maze. No difference from non-Tg at 2 months of age. Deficits in Y maze at 12 months. No deficit in fear conditioning up to 24 months of age.

Absent
  • Tangles at

    Absent.

  • Neuronal Loss at

    Qualitative difference in neuronal numbers at 24 months in specific regions of the hippocampus, but no significant neuronal loss.

  • Changes in LTP/LTD at

    At 12 to 14 months of age, deficits in basal synaptic transmission have been observed in the CA1 region, but short- and long-term synaptic plasticity are relatively normal (Brown et al., 2005).

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish) APP: Transgenic Alzheimer's Disease

Age-related accumulation of Aβ in the hippocampus and cortex leading to plaque deposition by 12 months of age. Early gliosis and dystrophic neurites, not limited to the vicinity around plaques. Changes in synaptic morphology and number, along with increased number of lysosomes.

Deficits in spatial memory prior to Aβ deposition, including deficits in the Morris water maze by 6 months Deficits in spontaneous alternation behavior in the Y maze by 12 months. No deficit in fear conditioning.

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TASTPM (TAS10 x TPM)

Observed
  1. X
    Plaques at 26

    Aβ begins to deposit at 3 months of age, with fibrillar plaques evident by 6 months in the cerebral cortex and hippocampus. Some vascular amyloid is also observed. Plaque pathology is more severe in female mice.

  2. X
    Gliosis at 28

    Greater numbers of reactive astrocytes and microglia by 6 months of age in the hippocampus and cortex, predominantly near amyloid plaques.

  3. X
    Cognitive Impairment at 26

    Age-dependent impairment in object recognition memory starting around 6 months of age for both sexes. No impairment at 3 to 4 months of age.

Absent
  • Tangles at

    Absent.

  • Neuronal Loss at

    Minimal neuronal loss up to 10 months of age. Some signs of loss in the immediate vicinity of plaques in the hippocampus (Howlett et al., 2008).

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1 M146V APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Aβ deposits beginning at 3 months of age, with fibrillar plaques by 6 months in the cerebral cortex and hippocampus. Some vascular amyloid. Plaques surrounded by dystrophic neurites and reactive glia. No tangles or neuronal loss. Female mice have more rapid and severe amyloid pathology.

Age-dependent impairment in object recognition memory starting around 6 months of age. 

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Tau35

Observed
  1. X
    Tangles at 35

    Abnormally phosphorylated tau detected at two months and by eight months tau was mislocalized and misfolded and dystrophic neurites were observed. Tangle-like structures observed in the hippocampus by 14 months.

  2. X
    Synaptic Loss at 61

    At 14 months synapsin1 protein levels were decreased but synaptophysin levels remained at wild-type levels.

  3. X
    Cognitive Impairment at 36

    In the Morris water maze, Tau35 had the same performance as wild-type animals at six months but developed progressive deficits by eight months. 

Absent
  • Gliosis at

    Gliosis was not observed at 14 months.

No Data
  • Plaques at

    Unknown.

  • Neuronal Loss at

    Cell death was not formally assessed, however, overt neuronal death was not seen in the hippocampus.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT: Transgenic Progressive Supranuclear Palsy, Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy

Progressive tau pathology in the hippocampus, including abnormally phosphorylated and misfolded tau, mislocalized tau, and tangle-like structures. Dystrophic neurites.

Impaired spatial learning and memory in the Morris water maze. Early motor impairments, including abnormal limb clasping, Rotarod deficits and decreased grip strength.

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Tau4RTg2652

Observed
  1. X
    Cognitive Impairment at 13

    Deficits in spatial learning and memory as indicated by performance in the Barnes maze at multiple time points (3, 6, 11 months of age).

Absent
  • Plaques at

    Absent.

  • Tangles at

    Absence of mature neurofibrillary tangles, but extensive pretangle pathology throughout the brain (e.g. phospho-tau).

  • Neuronal Loss at

    Absent.

No Data
  • Gliosis at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT: Transgenic Frontotemporal Dementia, Other Tauopathy, Alzheimer's Disease

Extensive pretangle pathology throughout the brain (e.g. phospho- tau) but no mature neurofibrillary tangles and only mild oligomeric tau, restricted to the CA1 region of the hippocampus. Dystrophic neurites and axonal pathology (spheroids). No overt neuronal loss.

Motor deficits develop with age, including decreased grip strength and impaired Rotarod performance. Cognitive deficits, indicative of impaired spatial learning and memory, as assessed by the Barnes maze.

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Tau609 (Tau 10 + 16)

Observed
  1. X
    Tangles at 65

    Gallyas silver-positive intracellular inclusions of hyperphosphorylated tau aggregates in the entorhinal cortex at 15 months, and in the hippocampus and cerebral cortex at 24 months, but not at 18 months.

  2. X
    Neuronal Loss at 65

    Significant loss of NeuN-positive neurons in layer II of the entorhinal cortex at 15 months, and in the hippocampal CA1 region at 24 months, compared with non-Tg controls. No difference in the hippocampus at 18 months.

  3. X
    Gliosis at 52

    At 12 months of age, Iba1-positive cells are observed. GFAP is observed at 24 months of age.

  4. X
    Synaptic Loss at 28

    Reduced synaptic density at 6 months of age in select hippocampal areas compared to non-Tg mice and those expressing wild-type human tau. Densities in other areas were comparable until later ages (i.e., 24 months).

  5. X
    Changes in LTP/LTD at 26

    Some changes in basal synaptic transmission and significant impairment of LTP evident by 6 months of age in some regions of the hippocampus.

  6. X
    Cognitive Impairment at 26

    Deficits in spatial reference memory by 6 months of age as measured by the Morris water maze. No difference from non-Tg littermates at 4 months of age.

Absent
  • Plaques at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT IVS10+16 C>T MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease, Other Tauopathy

Aggregated tau in neurons of the entorhinal cortex, hippocampus, and cerebral cortex at advanced ages. Intraneuronal accumulation of tau oligomers in the hippocampus. Neuronal loss in the entorhinal cortex and hippocampus. Gliosis. Some hippocampal areas affected by age-related synaptic dysfunction and reduced synaptic density.

Impaired spatial reference memory as measured by the Morris water maze by 6 months of age. 

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TauA152T-AAV

Observed
  1. X
    Neuronal Loss at 10

    Neuron loss in cortex, seen at 3 months.

  2. X
    Gliosis at 11

    Astrogliosis, but not microgliosis, seen at 3 months.

  3. X
    Cognitive Impairment at 12

    Deficits in contextual and cued fear conditioning, seen at 3 months.

Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT A152T MAPT: Virus Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy

Neuron loss and astrogliosis were observed in the cortices of 3-month-old mice.

Compared with GFP-AAV controls, TauA152T-AAV mice showed deficits in contextual and cued fear conditioning, increased hyperactivity, and decreased rearing in the open-field test, and spent more time in the open arms of the elevated plus maze. TauA152T-AAV mice also exhibited motor impairment on the Rotarod.

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TauC3 (Transgenic caspase-cleaved tau)

Observed
  1. X
    Synaptic Loss at 6

    Reduced levels of synaptic proteins as early as 1.3 months, including synaptophysin. Further reductions in 3 and 6-month-old animals.

  2. X
    Cognitive Impairment at 6

    Learning and memory impairments as early as 1.3 months in several behavioral tests including the Y-maze, passive avoidance, and novel object recognition.

Absent
  • Plaques at

    Amyloid plaques were absent.

  • Tangles at

    Neurofibrillary tangles were not observed; however, hyperphosphorylated tau occurred early in the form of oligomers and aggregates.

  • Neuronal Loss at

    No significant neurodegeneration by 12 months of age.

  • Gliosis at

    No significant astrogliosis in the hippocampus or cortex by 12 months of age.

No Data
  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia

No significant cell loss or astrogliosis in the brain. Age-dependent reduction in synaptic proteins (e.g. synaptophysin, PSD95) by 1.3 to 3 months of age. Hyperphosphorylated tau oligomers and aggregates.

Learning and memory deficits by 1.3 to 3 months of age, as assessed by the Y-maze and passive avoidance tests. No significant motor impairment.

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TauΔK280 ("Proaggregation mutant")

Observed
  1. X
    Tangles at 104

    Mature tangles are observed only at advanced age (>24 months), but extensive pre-tangle pathology develops with as little as three months of transgene expression. This includes mislocalization of tau to the somatodendritic compartment, conformational changes indicative of aggregation, and hyperphosphorylation (e.g. Ser 262, Ser 356).

  2. X
    Synaptic Loss at 57

    Electron microscopy showed a moderate decrease in spine synapses in the CA1 region of the hippocampus following 13 months of gene expression.

  3. X
    Changes in LTP/LTD at 52

    Impaired hippocampal LTP in the CA1 and CA3 areas.

  4. X
    Cognitive Impairment at 70

    Cognitive deficits in the Morris water maze and in passive-avoidance paradigms.

Absent
  • Plaques at

    Absent.

  • Neuronal Loss at

    Absent.

No Data
  • Gliosis at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT K280del MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia

Abundant pre-tangle pathology, but only rare mature tangles, and only at advanced ages. Tau pathology included mislocalization of tau to the somatodendritic compartment, aggregation, and hyperphosphorylation.

Unknown.

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Tau P301L

Observed
  1. X
    Tangles at 35

    Hyperphosphorylation, conformational changes, and aggregation of tau resulting in tangle-like pathology by 8 months.

  2. X
    Gliosis at 30

    Astrogliosis by 7 months.

  3. X
    Changes in LTP/LTD at 26

    Deficit in LTP in CA1 region of the hippocampus at 6 months, but enhanced LTP in the dentate gyrus at a young age (8-10 weeks).

  4. X
    Cognitive Impairment at 22

    Age-associated deficit in two cognitive tests that do not depend heavily on motor ability, the passive avoidance task (significant deficit starting at 5 months, but not 2 or 3 months of age) and a novel object recognition task (significant deficit at 9 months, but not at 2, 3, 5, or 7 months of age) (Maurin et al., 2014).

Absent
  • Plaques at

    Absent.

No Data
  • Neuronal Loss at

    Unknown.

  • Synaptic Loss at

    Unknown at advanced age. Young mice (1-2 months) have a significantly higher spine maturation index than controls. At 4-6 months, the spine maturation index remains high in the hippocampus, but is reduced to control levels in the cortex. Note, these results were generated using the progeny of Tau P301L x transgenic Thy1-YFP (Kremer et al., 2011).

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT P301L MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia

Pathologic hyperphosphorylation and conformational change of parenchymal tau in brain tissues starting at 7 months. Tangle-like pathology is mainly observed in the brain stem and spinal cord, and to a lesser extent in the midbrain and cerebral cortex. Age-dependent increase in total tau in CSF.

Age-associated deficits in a passive avoidance task (starting at 5 months) and a novel object recognition task (starting at 9 months). At a young age (~2 months) outperforms wild-type littermates in object recognition memory. Progressive motor impairment and reduced activity, accompanied by increased clasping of hind and then forelimbs around seven months.

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TauP301L-AAV

Observed
  1. X
    Tangles at 24

    Argyrophilic, Thioflavin S-positive neurofibrillary tangles in cortex and hippocampus.

  2. X
    Gliosis at 12

    Astrogliosis and microgliosis observed at 3 months.

  3. X
    Cognitive Impairment at 24

    Deficits in cued and contextual fear conditioning observed at 6 months.

Absent
  • Neuronal Loss at

    No cortical neuron loss at 6 months.

No Data
  • Plaques at

    No data.

  • Synaptic Loss at

    The accumulation of a PSD95 fragment suggests the possibility of synaptic abnormalities, although synaptic structure and function have not been assessed directly.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT P301L MAPT: Virus Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy

Neurofibrillary tangles and gliosis, but no cortical neuron loss, at 6 months of age.

Hyperactivity in the open field, decreased time spent in the center of open field, more time spent in the open arms of the elevated plus maze, and deficits in cued and contextual fear conditioning at 6 months of age.

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Tau P301S (Line PS19)

Observed
  1. X
    Tangles at 23

    Neurofibrillary tangles in the neocortex, amygdala, hippocampus, brain stem and spinal cord at six months with progressive accumulation (Yoshiyama et al., 2007).

  2. X
    Neuronal Loss at 39

    Neuron loss in the hippocampus and entorhinal cortex by nine to12 months, as well as in the amygdala and neocortex becoming more severe by 12 months (Yoshiyama et al., 2007).

  3. X
    Gliosis at 11

    Microgliosis at three months, especially in the white matter of the brain and spinal cord. Increased microgliosis by six months in white and gray matter of the hippocampus, amygdala, entorhinal cortex, and spinal cord. Microglial activation precedes astrogliosis (Yoshiyama et al., 2007).

  4. X
    Synaptic Loss at 13

    Synaptophysin immunoreactivity decreased progressively from three to six months in the CA3 region of the hippocamus. Impaired synaptic function (Yoshiyama et al., 2007).

  5. X
    Changes in LTP/LTD at 26

    Reduced LTP in the CA1 region of the hippocampus at six months. Altered basal synaptic transmission (smaller fiber volley amplitude, fEPSP slopes, and amplitudes) (Yoshiyama et al., 2007). Impaired hippocampal LTP as measured in freely moving mice (Lasagna-Reeves, 2016).

  6. X
    Cognitive Impairment at 27

    Impairments in spatial learning and memory ability in the Morris water maze in six-month-old animals (Takeuchi et al., 2011). Impaired memory in assays of contextual fear conditioning (Lasagna-Reeves 2016).

Absent
  • Plaques at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT P301S MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia

Neuron loss and brain atrophy by eight to 12 months, especially in the hippocampus and spreading to the neocortex and entorhinal cortex. Neurofibrillary tangles in the neocortex, amygdala, hippocampus, brain stem, and spinal cord. Neuroinflammation with microgliosis and astrocytosis.

Impairments in spatial memory and learning ability in Morris water maze. Paralysis at seven to 10 months associated with a hunched-back posture followed by feeding difficulties. About 80 percent mortality by 12 months with median survival of about nine months.

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TauPS2APP

Observed
  1. X
    Plaques at 17

    Rare amyloid plaques at 4 months, plaques become more abundant with age. By 8 months the number of amyloid plaques increases considerably in the subiculum and the CA1 region of the hippocampus (Grueninger et al., 2010).

  2. X
    Tangles at 70

    Abnormally phosphorylated tau is detectable at 4 months in both TauPS2APP and tau single transgenic mice especially in the subiculum, amygdala, and the CA1 region of the hippocampus. Tau pathology increases with age with numerous tangle-like deposits in the hippocampus confirmed by Gallyas silver staining at 16 months (Grueninger et al., 2010).

  3. X
    Cognitive Impairment at 17

    Impairment is not age-associated and does not progress from age 4 months to 12 months (Grueninger et al., 2010).

Absent
  • Neuronal Loss at

    No overt neuronal loss in the hippocampus at 16 months (Grueninger et al., 2010).

No Data
  • Gliosis at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, MAPT, PSEN2 APP K670_M671delinsNL (Swedish), MAPT P301L, PSEN2 N141I APP: Transgenic; MAPT: Transgenic; PSEN2: Transgenic Alzheimer's Disease

Phosphorylated tau accumulation in the subiculum and the CA1 region of the hippocampus at 4 months. Neurofibrillary tangles in these regions as well as the amygdala. Amyloid plaques. Dystrophic neurites and neuropil threads containing abnormally phosphorylated tau. No overt neuronal loss.

Impaired spatial learning in the Morris water maze at 4 months but impairment is not progressive between 4 and 12 months and appears to be independent of pathology.

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Tau R406W transgenic

Observed
  1. X
    Tangles at 78

    Congophilic tau inclusions in a subset of forebrain neurons around 18 months of age. Detected by Congo red, thioflavin S, and Gallyas silver stain.

  2. X
    Cognitive Impairment at 70

    Impairments in the contextual and cued fear conditioning test at 16–23 months compared with wild-type littermates. No detectable sensorimotor deficits.

Absent
  • Plaques at

    Absent.

No Data
  • Neuronal Loss at

    Unknown.

  • Gliosis at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT R406W MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease

Argyrophilic and congophilic tau inclusions in neurons of the forebrain with age. Detectable with Congo red, thioflavin-S and Gallyas silver stain. Congophilic tau inclusions also in the hippocampus and amygdala. Mainly straight tau filaments.

Impairments in contextual and cued fear conditioning at 16–23 months compared with wild-type littermates. No detectable sensorimotor deficits.

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TauRDΔK280 (“Proaggregation mutant”)

Observed
  1. X
    Tangles at 9

    Tau tangles and aggregates with as little as 2-3 months of transgene expression. Tangles start in the entorhinal cortex and amygdala and spread to the neocortex by 15 months. Heterogeneous tangle morphology, including flame-shaped.

  2. X
    Neuronal Loss at 22

    Neuronal loss in the dentate gyrus (granule neurons) following 5 months of transgene expression. Shrinkage of the molecular layer of the hippocampus.

  3. X
    Gliosis at 91

    Astrogliosis in the hilus region of the hippocampus after 21 months of transgene expression. Additional increases in GFAP-positive astrocytes in the entorhinal and piriform cortices.

  4. X
    Synaptic Loss at 41

    Hippocampal synaptic loss as indicated by multiple measures following 9.5 months of transgene expression. Reduced synaptophysin immunoreactivity and reduced number of spine synapses as measured by electron microscopy.

  5. X
    Changes in LTP/LTD at 43

    Multiple deficits in synaptic plasticity, including deficits in LTP and LTD, after 10 months of transgene expression. Functional changes are associated with structural synaptic changes, local calcium dysregulation, and a decrease in the synaptic vesicle pool.

  6. X
    Cognitive Impairment at 43

    Learning and memory impairments are apparent after 10 months of transgene expression as assessed by the Morris water maze and passive avoidance tasks.

Absent
  • Plaques at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT K280del MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia

Tau aggregates and tangles as early as 2-3 months after gene expression. Gallyas silver-positive neurons abundant in the entorhinal cortex and amygdala, spreading to the neocortex by 15 months. “Ballooned” neurons. Astrogliosis. Synaptic structural changes and reduced synaptic number. Hippocampal neuronal loss.

Reversible learning and memory deficits in the Morris water maze and passive avoidance test. No significant motor deficit, although slight reduction in Rotarod performance.

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Tau V337M

Observed
  1. X
    Tangles at 48

    Fibrillar staining in the hippocampus of 11 month old animals by Congo red birefringence. Absent in 4 month old mice, indicating the formation of these neurofilament-like structures occurs between 4 and 11 months (Tanemura et al., 2001).

  2. X
    Neuronal Loss at 43

    Evidence of hippocampal neuronal degeneration in 10 month old animals: irregularly shaped neurons with tau pathology that stained with propidium iodide. As characteristics of apoptosis were not observed, the neurons were thought to be undergoing non-apoptotic atrophic degeneration (Tanemura et al., 2002).

  3. X
    Changes in LTP/LTD at 65

    In hippocampal slices there was an attenuation of the amplitude of Schaffer collateral evoked hippocampal depolarization (Tanemura et al., 2002).

  4. X
    Cognitive Impairment at 48

    Behavioral abnormalities measured in 11 month-old mice. They spent more time in the open arms of the elevated plus maze and had greater overall locomoter activity. No differences in the Morris water maze compared with non-transgenic mice, suggesting the transgenic animals retain spatial recognition abilities (Tanemura et al., 2002).

Absent
  • Plaques at

    Absent.

No Data
  • Gliosis at

    Unknown.

  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT V337M MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia

SDS-insoluble tau aggregates in hippocampus. Degenerating neurons in the hippocampus containing phosphorylated and ubiquitinated tau aggregates with β-sheet structure.

Higher overall spontaneous locomotion than non-transgenic littermates in elevated plus maze. No differences in the Morris water maze.

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TBA42

Observed
  1. X
    Plaques at 52

    Very rare extracellular Aβ deposits.

  2. X
    Neuronal Loss at 52

    Age-dependent neuronal loss in the CA1 region of the hippocampus. No difference from wild-type mice at 3 and 6 months of age, but approximately 35% loss at 12 months of age.

  3. X
    Gliosis at 52

    Marked gliosis in the hippocampus as measured by GFAP staining at 12 months.

  4. X
    Cognitive Impairment at 54

    Age-dependent deficits in working and spatial reference memory at 12 months, but not at 3 and 6 months.

Absent
  • Tangles at

    Absent.

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP: Transgenic Alzheimer's Disease

Intraneuronal accumulation of Aβ peptides in the hippocampus by 3 months and in cerebellar nuclei by 6 months. Marked gliosis in the hippocampus by 12 months. Very rare extracellular Aβ deposits.

Age-dependent behavioral deficits, including working memory as assessed by the cross maze at 12 months, but not at 3 or 6 months. Early and persistent decrease in anxiety in the elevated plus maze. Comparable to wild-type in general motor coordination at 3 and 6 months as indicated by the balance-beam test, but impairment at 12 months.

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TcMAC21

Observed
  1. X
    Changes in LTP/LTD at 14

    Reduction in LTP compared to controls.

  2. X
    Cognitive Impairment at 13

    Behavioral (Morris water maze and open field) and physiological results showed significant deficits in learning, memory, and synaptic plasticity. No alteration in nesting abilities.

Absent
  • Plaques at

    At 15–24 months of age, no amyloid plaques detected.

No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Multi-transgene Down's Syndrome, Alzheimer's Disease

Elevated APP, Aβ40, and Aβ42 in brain at 15–24 months, but no amyloid plaque pathology. Enlarged lateral ventricles and superior colliculus, and smaller cerebellum.

Learning and memory deficits.

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Tg12099 rat

Observed
  1. X
    Tangles at 26

    Neurofibrillary tangles visualized by Bielschowsky silver staining were present in the piriform and entorhinal cortices of terminal Tg12099 rats homozygous for the transgene. Tangles also stained with ThioflavinS. Tangles were absent in hemizygous rats.

  2. X
    Neuronal Loss at 39

    Pronounced neurodegeneration in the forebrains of Tg12099 homozygotes at terminal stages. Neuronal loss and concordant atrophy of piriform/entorhinal cortices were first observed between 9 and 12 months and continued to worsen with age.

  3. X
    Gliosis at 27

    Increased GFAP immunoreactivity in the brains of terminal Tg12099 homozygotes compared with aged hemizygotes. Astrogliosis matches the spatiotemporal pattern of tau deposition, becoming apparent in the amygdala and entorhinal cortex as early as 6 to 7 months of age.

Absent
No Data
  • Plaques at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT P301S MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease

Tau pathology, including neurofibrillary tangles, forebrain neurodegeneration, and astrogliosis in homozygotes. Hemizygotes exhibit little pathology, save for a few AT8-immunoreactive neurons in the entorhinal cortices of aged animals.

Ataxia, bradykinesia, and seizures reported in aging homozygotes.

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Tg2576

Observed
  1. X
    Plaques at 48

    Numerous parenchymal Aβ plaques by 11-13 months.

  2. X
    Gliosis at 43

    Increase in microglial density and size in plaque-forming areas of the brain including the hippocampus, frontal cortex, entorhinal cortex, and occipital cortex in 10-16 month old hemizygotes (Frautschy et al., 1998).

  3. X
    Synaptic Loss at 20

    Dendritic spine loss by 4.5 months In the CA1 region of the hippocampus (Lanz et al., 2003).

  4. X
    Changes in LTP/LTD at 22

    By 5 months, there was a decline in LTP in the dentate gyrus after perforant path stimulation compared to wild-type; impairment was not observed at 2 months (Jacobsen et al., 2006). Both the CA1 and dentate gyrus of aged mice (>15 months) are impaired (Chapman et al., 1999). Differences have been observed between the Schaffer collateral and mossy fiber pathways (Jung et al., 2011).

  5. X
    Cognitive Impairment at 26

    Impaired spatial learning, working memory, and contextual fear conditioning at <6 months although other studies have reported normal cognition at this age with progressive impairment by >12 months.

Absent
  • Tangles at

    Absent.

  • Neuronal Loss at

    Absent or very limited.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish) APP: Transgenic Alzheimer's Disease

Numerous parenchymal Aβ plaques by 11-13 months with some vascular amyloid. Oxidative lipid damage, astrogliosis and microgliosis. No tangles or neuronal loss.

Impaired spatial learning, working memory, and contextual fear conditioning reported at <6 months although other studies have reported normal cognition at this age with progressive impairment by >12 months.

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Tg2576/Tau(P301L) (APPSwe-Tau)

Observed
  1. X
    Plaques at 39

    Plaques develop gradually with age. No plaques at 5 months. Very few small plaques at 6 and 7 months. By 9 months plaques scattered throughout the cortex, hippocampus and amygdala, continue to increase at 12 months. Similar distribution as Tg2576.

  2. X
    Tangles at 13

    Neurofibrillary tangles in the spinal cord and pons as early as 3 months, but more consistent and numerous by 6 months. Tangles morphologically similar to those in JNPL3 mice but older bigenic female mice had a marked increase in neurofibrillary tangles in limbic areas by 6 months, especially the olfactory cortex, entorhinal cortex and amygdala (Lewis et al., 2001).

  3. X
    Gliosis at 13

    Reactive astrocytes and microglia as early as 3 months in the hippocampus as measured by GFAP and CD45. Increased astrocytosis with age especially in limbic areas with the most neurofibrillary tangles. Microglia especially concentrated around plaques at 9 and 12 months (Lewis et al., 2001).

Absent
No Data
  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, MAPT APP K670_M671delinsNL (Swedish), MAPT P301L APP; MAPT: Transgenic Alzheimer's Disease

Gradual appearance of plaques; by 9 months plaques are scattered throughout the cortex, hippocampus, and amygdala similar to Tg2576. Tau pathology more extensive than JNPL3. Astrocytosis and microgliosis.

Motor disturbances similar to JNPL3, with identical range in age of onset. Reduced vocalization and decreased grooming.

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Tg4-42

Observed
  1. X
    Neuronal Loss at 35

    Age- and dose-dependent neuronal loss in the hippocampus CA1 region of hemizygous and homozygous mice. Compared with wild-type, hemizygous mice had 38% neuronal loss at 8 months, and 49% loss at 12 months. No difference at 3 months.

  2. X
    Gliosis at 9

    Reactive microglia and astrocytes in the hippocampus starting at 2 months.

  3. X
    Synaptic Loss at 37

    Altered synaptophysin staining in the CA3 region of the hippocampus. More pronounced in homozygous mice than hemizygous mice at 8 months.

  4. X
    Cognitive Impairment at 35

    Spatial reference memory is impaired as assessed by Morris water maze at 8 months in homozygous mice and 12 months in hemizygous mice. Deficit is age-dependent and is not detected at 3 months. Impaired contextual fear conditioning at 12 months.

Absent
  • Plaques at

    Absent.

  • Tangles at

    Absent.

No Data
  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP: Transgenic Alzheimer's Disease

Aβ4-42 is dectable starting at two months, predominantly in the CA1 region of the hippocampus, but also in the occipital cortex, piriform cortex, striatum, and superior colliculus. Age- and dose-dependent hippocampal neuronal loss is seen in the CA1 region as well as microgliosis and astrogliosis.

Age-dependent spatial learning deficit as demonstrated in the Morris water maze, specifically, the absence of a preference for the target quadrant starting at eight months in homozygous mice and at 12 months in hemizygous mice. Impaired contextual fear conditioning.

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tg-APPSwe

Observed
  1. X
    Plaques at 52

    Plaques are detectable at approximately 12 months and are heterogeneous in morphological structure and size, as well as in terms of fluorescence emitted when stained with luminescent polymers (conformational amyloid ligands)(Philipsson et al., 2009).

  2. X
    Gliosis at 52

    Microgliosis and astrogliosis are most prominent in the hippocampus, but also found locally around deposits in the cerebral cortex and in thalamus at approximately 12 months (Philipsson et al., 2009).

Absent
  • Tangles at

    Absent.

  • Neuronal Loss at

    Absent.

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

  • Cognitive Impairment at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish) APP: Transgenic Alzheimer's Disease

Extracellular amyloid deposition begins at ~12 months. Intraneuronal Aβ aggregates at ~6 months. Extracellular pathology, both cerebrovascular amyloid angiopathy (CAA) and congophilic parenchymal plaques, mainly found in the cerebral cortex, hippocampus and thalamus. Aβ-burden in cerebral cortex is approximately 1.0% (at 12 months) and 2.8% (at 18 months).

Unknown.

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Tg-ArcSwe

Observed
  1. X
    Plaques at 22

    Extracellular amyloid plaque deposition starts at around 5-6 months of age (Lord et al., 2006) and is most consistently present in the cerebral cortex, hippocampus, and thalamus (Lillehaug et al., 2013).

  2. X
    Gliosis at 26

    Microgliosis and astrogliosis most prominent in the hippocampus, but also locally around deposits in the cerebral cortex and thalamus.

  3. X
    Cognitive Impairment at 17

    Transgene-dependent spatial learning impairment in the Morris water maze (4-8 months) (Lord et al., 2009) and in an Intellicage-based Passive Avoidance test (16 months)(Codita et al., 2010).

Absent
  • Tangles at

    Absent.

  • Neuronal Loss at

    Absent.

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish), APP E693G (Arctic) APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy

Strong intraneuronal Aβ aggregation starting at 1 month and increasing with age. Extracellular amyloid plaque at 5-6 months, most consistent in the cerebral cortex, hippocampus, and thalamus. Congophilic parenchymal plaques are predominant, but some mice show marked CAA, particularly in the thalamus.

Mild spatial learning deficits at 4-8 months in Morris water maze and impaired functioning in a passive avoidance test at 16 months.

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TgCRND8

Observed
  1. X
    Plaques at 13

    Amyloid deposition progresses with age. Thioflavin S-positive amyloid deposits at 3 months; dense cored plaques and neuritic pathology by 5 months. Plaques appear first in the subiculum, amygdala and frontal cortex, spread to the dentate gyrus, the olfactory bulb, and later thalamus, cerebral vasculature, and striatum, followed by the cerebellum and brain stem (Chishti et al., 2001).

  2. X
    Neuronal Loss at 26

    Variable cell loss by region. No difference in overall cell count, but fewer hippocampal neurons at 6 months (Brautigam et al., 2012).

  3. X
    Gliosis at 13

    Microglia activation appears simultaneously with Aβ deposition, with only rare activated microglia at 9-10 weeks, but by 13-14 weeks microglia cluster around Aβ deposits in the cerebral cortex and hippocampus; numerous by 20 weeks. Robust astrogliosis slightly later with clusters of GFAP+ astrocytes emerging around plaques at 13-14 weeks (Dudal et al., 2004).

  4. X
    Synaptic Loss at 26

    Reduced synaptophysin immunoreactivity in the vicinity of plaques at 6 months (Adalbert et al., 2009).

  5. X
    Changes in LTP/LTD at 26

    In hippocampal slices from 6- to 12-month-old mice basal excitatory synaptic transmission (as assessed by I/O relationships) and LTP at CA1 are reduced in TgCRND8 mice compared with wild-type mice (Kimura et al., 2012).

  6. X
    Cognitive Impairment at 13

    Early impairment in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months (Chishti et al., 2001).

Absent
  • Tangles at

    Neurofibrillary tangles are absent (Chishti et al., 2001). Tau is hyperphosphorylated, nitrosylated and aggregated at 7-12 months especially in the neocortex, dentate gyrus, and the CA1 and CA3 areas of the hippocampus (Bellucci et al., 2007).

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish), APP V717F (Indiana) APP: Transgenic Alzheimer's Disease

Rapid, early plaque development, with thioflavin S-positive amyloid deposits at 3 months; dense cored plaques and neuritic pathology by 5 months. Plaques become more extensive with age. More Aβ42 than Aβ40. Activated microglia appear concurrently with plaques, whereas GFAP+ astrocytes follow later, about 13-14 weeks. Dystrophic neurites at 5 months .

Early impairment in acquisition and learning reversal in the reference memory version of the Morris water maze by 3 months. Cognitive deficits in the step-down inhibitory avoidance test at 7 months but not at 2 months. Similar to wild-type in motility, exploratory activity, or neuromuscular function at 7 months as evaluated by the rotarod, hole board and grip strength tests.

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TgDimer

Observed
  1. X
    Changes in LTP/LTD at 28

    LTP decays more rapidly, compared with wild-type mice.

  2. X
    Cognitive Impairment at 28

    Learning deficits in the Morris Water Maze.

Absent
  • Plaques at

    None observed through 24 months.

  • Tangles at

    None observed through 24 months.

  • Neuronal Loss at

    None observed through 24 months.

  • Gliosis at

    No transgene-related gliosis, but slight age-associated gliosis—also seen in wild-type mice—at 24 months.

No Data
  • Synaptic Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish), APP S679C APP: Transgenic Alzheimer's Disease, MCI due to AD

Intracellular Aβ immunoreactivity in the hippocampus and cortex, beginning by 12 months. No amyloid plaques, hyperphosphorylated tau, microgliosis, astrogliosis, or neuron loss through 24 months.

Learning deficits, as well as indicators of increased anxiety and depression, by 7 months.

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TgF344-AD

Observed
  1. X
    Plaques at 24

    Age-dependent accumulation of amyloid plaques in hippocampus and cortex between 6 and 26 months of age.

  2. X
    Tangles at 64

    Structures similar in appearance to neurofibrillary tangles revealed by Gallyas staining and immunostaining using an antibody directed against phospo-tau.

  3. X
    Neuronal Loss at 64

    Approximate 40 percent loss of neurons in hippocampus and cortex by 16 months.

  4. X
    Gliosis at 23

    Microgliosis and astrogliosis are apparent by 6 months.

  5. X
    Cognitive Impairment at 25

    Deficits in reversal learning in the Morris water maze apparent by 6 months.

Absent
No Data
  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques, microgliosis, and astrogliosis by 6 months. Neurofibrillary tangle-like structures at 16 months. Approximate 40 percent loss of neurons in hippocampus and cortex by 16 months.

Earliest reported deficits are in reversal learning in the Morris water maze, apparent by 6 months.

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Tg-SwDI (APP-Swedish,Dutch,Iowa)

Observed
  1. X
    Plaques at 13

    Hemizygotes progressively accumulate insoluble Aβ40 and Aβ42, especially within brain microvessels starting at 3 months. Amyloid-β deposits in the subiculum, hippocampus, and cortex at ~3 months. By ~6 months deposits become more numerous and appear in the olfactory bulb and thalamic region as well, with deposits throughout most of the forebrain by 12 months (Davis et al., 2004).

  2. X
    Gliosis at 26

    Pronounced increase in the number of GFAP-positive astrocytes and activated microglia with age (6-24 months) especially in the thalamus and subiculum and to a lesser extent in the cortex (Miao et al., 2005).

  3. X
    Cognitive Impairment at 13

    Impaired learning and memory in the Barnes maze task at 3, 9, and 12 months; beginning at 3 months took longer to find the escape hole. No difference in mobility, strength or coordination (Xu et al., 2007).

Absent
  • Tangles at

    Absent.

No Data
  • Neuronal Loss at

    Unknown.

  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP K670_M671delinsNL (Swedish), APP E693Q (Dutch), APP D694N (Iowa) APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type

Hemizygotes progressively accumulate insoluble Aβ40 and Aβ42, especially within brain microvessels starting at 3 months. Fibrillar Aβ in micovessels around 6 months. Diffuse plaque-like deposits around 3 months in the subiculum, hippocampus and cortex. Aβ deposits throughout the forebrain by 12 months.

Impaired learning and memory in the Barnes maze task at 3, 9, and 12 months. Beginning at 3 months transgenic mice took longer to find the escape hole. No difference in mobility, strength or coordination.

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THY-Tau22

Observed
  1. X
    Tangles at 13

    Heterozygous animals develop tau pathology starting at 3-6 months. Pathology becomes more severe and widespread with age. Neurofibrillary tangle-like inclusions occur (Gallyas and MC1+) along with rare ghost tangles and paired helical filament-like structures (Schindowski et al., 2006).

  2. X
    Neuronal Loss at 52

    Loss of cells in the CA1 region of the hippocampus from 12 months as measured by DAPI staining and Nissl/cresyl-violet (Schindowski et al., 2006). Also, a significant reduction in the number of choline acetyltransferase (ChAT)-immunopositive cholinergic neurons in the medial septum has been reported (Belarbi et al., 2011).

  3. X
    Gliosis at 13

    Age-dependent increase in the number of GFAP+ astrocytes in the hippocampus (hilus, CA1, CA3), cerebral cortex, corpus callosum (Schindowski et al., 2006).

  4. X
    Changes in LTP/LTD at 39

    Altered paired pulse facilitation (PPF), a form of presynaptic short-term plasticity in 9-10 month old heterozygous animals: PPF increased at 10 ms. Also at this age, impaired maintenance of long term depression as compared with wild-type littermates (Van der Jeugd et al., 2011). Deficit in basal synaptic transmission in the hippocampus, but normal LTP (Schindowski et al., 2006).

  5. X
    Cognitive Impairment at 26

    Non-spatial memory affected as early as 6 months; spatial memory impaired only after 9 months (Van der Jeugd et al., 2013). Impaired appetitive responding (Lo et al., 2013).

Absent
  • Plaques at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT G272V, MAPT P301S MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease

A variety of tau pathologies starting at 3 months, including neurofibrillary tangle-like inclusions, rare ghost tangles, and paired helical filament-like structures. Hyperphosphorylation of tau on many epitopes (e.g. AT8, AT100, AT180, AT270, 12E8, tau-pSer396, and AP422) and mild astrogliosis.

Increased anxiety and delayed learning from 3 months, and reduced spatial memory at 10 months. No changes in overall motor activity and no gross motor deficits. Increased depression-like and aggressive behavior, co-occurring with disturbances in nocturnal activity.

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TMHT (Thy-1 mutated human tau)

Observed
  1. X
    Tangles at 17

    Tangles at 4 months and progress with age.

  2. X
    Cognitive Impairment at 22

    Cognitive impairment by 5 months as measured by the Morris Water Maze.

Absent
  • Plaques at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT V337M, MAPT R406W MAPT: Transgenic Alzheimer's Disease

Increased total tau, and phosphorylated tau (Thr181, Ser199, Thr231) in amygdala and hippocampus starting at 3 months.

Spatial memory deficits starting at 5 months (Morris water maze). Olfactory deficits at 5 months (Buried food test). No motor deficits (rota rod, beam walk) or depressive behavior (forced swim test).

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TREM2-BAC

Observed
Absent
  • Plaques at

    Not observed at 7 months.

  • Gliosis at

    No microgliosis was observed at 7 months.

  • Changes in LTP/LTD at

    Normal LTP at 10 months.

  • Cognitive Impairment at

    Normal contextual fear conditioning at 10 months.

No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TREM2 TREM2: Transgenic Alzheimer's Disease

No obvious neuropathology is observed at 4, 7 and 11 months of age.

Normal contextual fear conditioning at 10 months of age.

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TREM2-BAC X 5xFAD

Observed
  1. X
    Plaques at 28

    Observed at 7 months, the youngest age examined.

  2. X
    Gliosis at 28

    Microgliosis observed; however, fewer plaque-associated microglia and altered microglial morphology (more ramified processes) compared with 5xFAD at 7 months, the only age examined.

Absent
  • Cognitive Impairment at

    5xFAD/TREM2 mice perform comparably to wild-type mice in a contextual fear conditioning test, while 5xFAD mice are impaired.

No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TREM2, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V TREM2: Transgenic; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques with plaque-associated microgliosis. Reduced plaque burden, altered microglial and plaque morphology, and less severe plaque-associated neuritic dystrophy, compared with 5xFAD.

5xFAD/TREM2 mice perform comparably to wild-type mice in a contextual fear conditioning test, while 5xFAD mice are impaired.

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Trem2-H157Y knock-in

Observed
  1. X
    Changes in LTP/LTD at 24

    Enhanced paired-pulse facilitation and long-term potentiation at Schaffer collateral-CA1 synapses in 6-month-old mice homozygous for the H157Y Trem2 allele.

Absent
  • Gliosis at

    Microglial density and morphology did not differ between carriers of the H157Y variant and wild-type mice at 6 months of age.

  • Synaptic Loss at

    Levels of the presynaptic marker synaptophysin and the postsynaptic markers PSD95 and GLUR2 in the cortices of 6-month-old mice did not differ between carriers of the H157Y variant and wild-type mice.

  • Cognitive Impairment at

    The H157Y mutation did not affect the performances of 6-month-old mice on a battery of behavioral tests: the open-field test to assess anxiety, cued and contextual fear conditioning to measure associative memory, and the Y-maze test to measure spatial working memory.

No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2 TREM2 H157Y Trem2: Knock-In Alzheimer's Disease

Microglial density and morphology did not differ between carriers of the H157Y variant and wild-type mice.

Trem2-H157Y knock-in did not differ from wild-type mice at 6 months of age in tests of anxiety, associative memory, and spatial working memory.

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Trem2-H157Y x 5xFAD

Observed
  1. X
    Plaques at 16

    Decreased plaque burdens and densities in 5xFAD;Trem2H157Y/H157Y compared with 5xFAD;Trem2+/+ at 8.5 months, but genotypes similar at 4 months.

  2. X
    Gliosis at 16

    Decreased microgliosis and astrogliosis in 5xFAD;Trem2H157Y/H157Y compared with 5xFAD;Trem2+/+ at 8.5 months, but genotypes similar at 4 months.

Absent
  • Synaptic Loss at

    Cortical levels of synaptophysin and PSD95 did not differ between genotypes at 8.5 months.

No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2, APP, PSEN1 TREM2 H157Y, APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V Trem2: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Age-dependent effects on amyloid-β pathology and gliosis. At 4 months, plaque burdens, microgliosis, and astrogliosis were similar among genotypes. By 8.5 months, amyloid burdens, microgliosis, and astrogliosis were reduced in homozygous carriers of the H157Y variant, compared with 5xFAD mice homozygous for wild-type Trem2.

Unknown.

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TREM2, humanized (common variant)

Observed
Absent
  • Gliosis at

    Expression of DAM (disease-associated microglia) genes is low at 8.5 months, suggesting that microglia are in a resting or homeostatic state.

No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TREM2, Trem2 TREM2: Transgenic; Trem2: Knock-Out Alzheimer's Disease

Unknown.

Unknown.

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TREM2, humanized (common variant) X 5XFAD

Observed
  1. X
    Plaques at 34

    Plaques observed in 8.5-month-old mice, only age reported thus far.

  2. X
    Gliosis at 34

    Microgliosis observed in 8.5-month-old mice, only age reported thus far.

Absent
No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2, TREM2, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V Trem2: Knock-Out; TREM2: Transgenic; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques surrounded by activated microglia.

No data.

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TREM2, humanized (R47H)

Observed
Absent
  • Gliosis at

    Expression of DAM (disease-associated microglia) genes is low at 8.5 months, suggesting that microglia are in a resting or homeostatic state.

No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
TREM2, Trem2 TREM2 R47H TREM2: Transgenic; Trem2: Knock-Out Alzheimer's Disease

Unknown.

Unknown.

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TREM2, humanized (R47H) X 5XFAD

Observed
  1. X
    Plaques at 34

    Plaques observed in 8.5-month-old mice, the only age reported thus far.

  2. X
    Gliosis at 34

    Microgliosis observed in 8.5-month-old mice, the only age reported thus far. Fewer plaque-associated microglia in mice expressing the R47H variant, compared with the common variant of human TREM2.

Absent
No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2, TREM2, APP, PSEN1 TREM2 R47H, APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V Trem2: Knock-Out; TREM2: Transgenic; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Lower density of activated microglia surrounding amyloid plaques in 5XFAD mice expressing the R47H variant of human TREM2 compared with those expressing the common variant.

No data.

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TREM2-IPD

Observed
  1. X
    Gliosis at 12

    At 3 months of age, TREM2-IPD mice had more Tmem119-positive microglia and a greater percentage of proliferating microglia than mice expressing wild-type Trem2.

Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2 Trem2: Knock-In Alzheimer's Disease

At 3 months of age, TREM2-IPD mice had more Tmem119-positive microglia and a greater percentage of proliferating microglia than mice expressing wild-type Trem2.

Unknown.

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Trem2-IPDxAPP23xPS45

Observed
  1. X
    Plaques at 12

    Greater numbers of plaques, particularly small plaques, and larger areas occupied by plaques in 3-month-old Trem2-IPDxAPP23xPS45 mice, compared with APP23xPS45 animals. These genotype-dependent differences disappeared by 7 months.

  2. X
    Gliosis at 13

    Increased microgliosis in the vicinity of plaques in 3-month-old Trem2-IPDxAPP23xPS45 mice, compared with APP23xPS45 mice.

  3. X
    Synaptic Loss at 14

    Compared with APP23xPS45 mice, 3-month-old Trem2-IPDxAPP23xPS45 mice had fewer and smaller puncta stained for the presynaptic marker Sv2a (synaptic vesicle glycoprotein 2A) in the vicinity of plaques. These genotype-dependent differences disappeared  by 7 months.

Absent
No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2, APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1 G384A Trem2: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques, plaque-associated neuritic dystrophies, microgliosis. Pathology exacerbated in Trem2-IPDxAPP23xPS45 mice, compared with APP23xPS45 mice expressing wild-type Trem2, at an early—but not late—stage of plaque deposition.

Unknown.

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Trem2 KO (Colonna)

Observed
Absent
  • Gliosis at

    No spontaneous gliosis, but impaired microglial response to injury.

  • Cognitive Impairment at

    Not observed.

No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2 Trem2: Knock-Out Nasu-Hakola Disease, Frontotemporal Dementia, Alzheimer's Disease

Microglial number remains constant and microglial size decreases with age in the corpus callosum of Trem2 KO mice, while microglial number increases and microglial size remains stable in wild-type mice.

No cognitive/behaviorial deficits observed.

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Trem2 KO (Colonna) x 5XFAD

Observed
  1. X
    Plaques at 16

    Plaques present by 4 months, the earliest age studied.

  2. X
    Neuronal Loss at 32

    Loss of cortical layer V neurons by 8 months, the earliest age studied.

  3. X
    Gliosis at 16

    MIcrogliosis by 4 months, the earliest age studied.

Absent
No Data
  • Tangles at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2, APP, PSEN1 APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V Trem2: Knock-Out; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Compared with 5XFAD, mice deficient in TREM2 show an age- dependent increase in amyloid accumulation in the hippocampus, more severe plaque-associated neuritic dystrophy, and exaggerated neuron loss in the cortex. Microglial containment of plaques is compromised in TREM2-deficient animals. Microglia accumulate autophagosomes.

No data.

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Trem2 KO (Colonna) x PS19

Observed
  1. X
    Gliosis at 36

    Microgliosis and astrogliosis by 9 months (the earliest age studied).

Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2, MAPT MAPT P301S Trem2: Knock-Out; MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease

Microgliosis, astrogliosis, and brain atrophy in Trem2-/-PS19 mice are greatly attenuated compared with Trem2+/+PS19 animals.

No data.

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Trem2 KO (JAX)

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2 Trem2: Knock-Out Alzheimer's Disease, Frontotemporal Dementia, Nasu-Hakola Disease

No data..

No data.

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Trem2 KO (KOMP)

Observed
Absent
  • Cognitive Impairment at

    At six months, mice perform normally in the open-field test, elevated plus maze, three-chamber social-interaction test, and contextual and cued fear-conditioning test.

No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2 Trem2: Knock-Out Nasu-Hakola Disease, Frontotemporal Dementia, Alzheimer's Disease

No data.

At six months, mice perform normally in the open-field test, elevated plus maze, three-chamber social-interaction test, and contextual and cued fear-conditioning test.

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Trem2 KO (KOMP) x APPPS1

Observed
  1. X
    Plaques at 9

    Plaques are observed by 2 months.

  2. X
    Gliosis at 9

    Gliosis is observed by 2 months.

Absent
No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2, APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1 L166P Trem2: Knock-Out; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Reduced plaque burden at early stages of plaque deposition but increased plaque burden at later stages, fewer plaque-associated myeloid cells and astrocytes, less phospho-tau in plaque-associated dystrophic neurites, compared with APPPS1.

No data.

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Trem2 KO (KOMP) x htau

Observed
  1. X
    Gliosis at 24

    Microgliosis observed by 6 months, younger ages were not studied.

Absent
  • Neuronal Loss at

    Neuron loss not observed in cortex or hippocampal field CA3 at 6 months of age; later ages were not studied.

No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Mapt, MAPT, Trem2 Mapt: Knock-Out; MAPT: Transgenic; Trem2: Knock-Out Nasu-Hakola Disease, Alzheimer's Disease, Frontotemporal Dementia

Tau phosphorylation and aggregation in the cortex are enhanced in htau mice lacking TREM2, but reactive microglia are smaller and their processes have fewer branches.

No data.

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Trem2*R47H(HSS)

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2 TREM2 R47H Trem2: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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Trem2 R47H KI (Haass)

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2 TREM2 R47H Trem2: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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Trem2 R47H KI (JAX)

Observed
Absent
  • Plaques at

    Not observed in cortex or hippocampus up to 24 months of age.

  • Tangles at

    Not observed in cortex or hippocampus up to 24 months of age.

  • Neuronal Loss at

    Not observed in cortex or hippocampus up to 24 months of age.

  • Cognitive Impairment at

    Locomotor activity, motor coordination, and working memory similar to wild-type at 2 and 12 months of age.

No Data
  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2 TREM2 R47H Trem2: Knock-In Alzheimer's Disease

No neuron loss, amyloid plaques, or neurofibrillary tangles were observed in mice up to 24 months of age.

Locomotor activity, motor coordination, and working memory similar to wild-type at 2 and 12 months of age.

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Trem2 R47H KI (Lamb/Landreth)

Observed
Absent
  • Plaques at

    No 6E10- or Thioflavin S-positive amyloid plaques were observed at 4 months of age.

No Data
  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2 TREM2 R47H Trem2: Knock-In Alzheimer's Disease

No 6E10- or Thioflavin S-positive amyloid plaques were observed at 4 months of age.

Unknown.

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Trem2 R47H KI (Lamb/Landreth) X APPPS1-21

Observed
  1. X
    Plaques at 16

    Reduction in the number and burden of fibrillar amyloid plaques in the hippocampus, compared with APPPS1-21 mice homozygous for wild-type Trem2.

  2. X
    Gliosis at 16

    Fewer plaque-associated myeloid cells in APPPS1-21;Trem2+/R47H, compared with APPPS1-21 mice homozygous for wild-type Trem2.

Absent
  • Tangles at

    Tangles were not observed at 4 months of age, but hyperphosphorylated tau was detected in dystrophic neurites surrounding plaques.

  • Neuronal Loss at

    No differences in neuron number in cotical layer V in APPPS1-21;Trem2+/R47H mice relative to APPPS1-21 mice homozygous for wild-type Trem2, at 4 months of age.

No Data
  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2, APP, PSEN1 TREM2 R47H, APP K670_M671delinsNL (Swedish), PSEN1 L166P Trem2: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Reduction in the number and burden of fibrillar amyloid plaques in the hippocampus, fewer plaque-associated myeloid cells, and worse plaque-associated neuritic dystrophy, compared with APPPS1-21 mice homozygous for wild-type Trem2.

Unknown.

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Trem2 R47H KI x APOE4 (LOAD1)

Observed
Absent
  • Plaques at

    Not observed in cortex or hippocampus up to 24 months of age.

  • Tangles at

    Not observed in cortex or hippocampus up to 24 months of age.

  • Neuronal Loss at

    Not observed in cortex or hippocampus up to 24 months of age.

  • Gliosis at

    Microgliosis not observed in cortex or hippocampus up to 24 months of age.

  • Cognitive Impairment at

    Age-related changes in locomotor activity, motor coordination, and working memory, but no genotype-dependent differences through 24 months of age, compared with wild-type mice.

No Data
  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE, Trem2 TREM2 R47H, APOE C130R (ApoE4) APOE: Knock-In; Trem2: Knock-In Alzheimer's Disease

No neuron loss, amyloid plaques, neurofibrillary tangles, vascular leakage, myelin loss, or reactive microglia in mice up to 24 months of age.

Age-related changes in locomotor activity, motor coordination, and working memory, but no genotype-dependent differences through 24 months of age, compared with wild-type mice.

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Trem2 R47H knock-in

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2, App TREM2 R47H Trem2: Knock-In; App: Knock-In Alzheimer's Disease

Unknown.

Unknown.

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Trem2*R47H(NSS)

Observed
  1. X
    Synaptic Loss at 50

    Synapse loss, assessed by co-localization of the pre-synaptic marker bassoon and postsynaptic marker PSD95, by 12 months.

  2. X
    Changes in LTP/LTD at 52

    Impaired basal synaptic transmission and LTP, by 12 months.

Absent
  • Plaques at

    Not observed.

  • Tangles at

    Not observed.

  • Gliosis at

    Similar numbers of Iba1-immunoreactive microglia in Trem2*R47HNSS and wild-type hippocampi and cortices, but differences in microglial morphology at 4 months that are gone by 12 months.

No Data
  • Neuronal Loss at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2 TREM2 R47H Trem2: Knock-In Alzheimer's Disease

Changes in microglial morphology at 4 months but not 12 months, compared with wild-type.

Unknown.

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TREM2-sol

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2 Trem2: Knock-In None

Unknown.

Unknown.

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Trem2 T66M KI

Observed
  1. X
    Gliosis at 30

    Fewer clusters of Iba1-immunoreactive microglia in Trem2 T66M mice compared with wild-type mice, becoming statistically significant at 7 months of age.

Absent
  • Plaques at

    Not observed.

  • Tangles at

    Not observed.

No Data
  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2 TREM2 T66M Trem2: Knock-In Frontotemporal Dementia

Age-related microglial activation seen in wild-type mice is absent in homozygotes.

No data.

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Trem2 Y38C KI

Observed
Absent
No Data
  • Plaques at

    No data.

  • Tangles at

    No data.

  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Trem2 TREM2 Y38C Trem2: Knock-In Frontotemporal Dementia

No data.

No data.

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Ts65Dn

Observed
  1. X
    Neuronal Loss at 26

    By 6 months, there is a loss of basal forebrain cholinergic neurons in the medial septal nucleus. From 10-11 months, a decrease in ChAT+ motor neurons are observed. Additional deficits include reduced brain volume, impaired neurogenesis, decreased neuronal density, and abnormal dendritic spine morphology, which are present in earlier stages of development.

  2. X
    Gliosis at 42

    Ts65Dn mice show a developmental shift from neuronal to astrocytic lineage, leading to an increased percentage of astroglial cells in the cortex and hippocampus. By 10 to 18 months, an elevated density of CD45+ microglia cells are found in the hippocampus and basal forebrain, with IBA1 upregulation at 12 months and reduced expression of the homeostatic microglial marker P2RY12 at 15 months.

  3. X
    Synaptic Loss at 65

    Ts65Dn mice have more inhibitory synapses, and fewer excitatory synapses. Synaptic density is decreased in both the hippocampus and neocortex, accompanied by enlarged pre-synaptic boutons and spines. Changes in the physical distribution of afferent inputs also occur.

  4. X
    Changes in LTP/LTD at 26

    Ts65Dn mice demonstrate impaired hippocampal long-term potentiation (LTP) due to excessive GABA-mediated inhibition.

  5. X
    Cognitive Impairment at 13

    Ts65Dn mice exhibit reduced attention, and deficits in hippocampal-dependent functions, including contextual fear conditioning, working memory, and long-term spatial memory.

Absent
  • Plaques at

    Although Ts65Dn mice exhibit age-related increase in APP and Aβ levels in the cortex and hippocampus, they do not show plaque pathology. However, an increase in soluble Aβ oligomers and small amyloidal extracellular inclusions in the deep granular cell layer of the cerebellum has been reported.

  • Tangles at

    Although Ts65Dn mice exhibit increased tau phosphorylation, they do not develop neurofibrillary tangles.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Multi-transgene Down's Syndrome, Alzheimer's Disease

Elevation of APP and soluble Aβ in the brain without Aβ plaque pathology. Changes to tau 3R/4R splicing, augmenting tau mRNA stability and tau phosphorylation. Basal forebrain neurodegeneration; loss of NE neurons in locus coeruleus; hippocampal abnormalities; cholinergic neuron loss; reduced number of proliferating cells. Neuroinflammation and oxidative stress markers.

Spatial learning and memory deficits, developmental delay in sensorimotor milestones, locomotor hyperactivity, lack of behavioral inhibition, and stereotypic behavior. Delayed motor acquisition, impaired coordination,  reduced attention.

expand

WSB.APP/PS1

Observed
  1. X
    Plaques at 32

    Thioflavin S-positive amyloid plaques are present in the cortex and CA1 region of the hippocampus by 8 months of age, with females having more plaques in the cortex than males.

  2. X
    Neuronal Loss at 34

    Compared with their non-transgenic littermates, female WSB.APP/PS1 mice have fewer neurons in the cortex and in CA1. Neuron numbers in male mice do not differ between the genotypes.

  3. X
    Gliosis at 33

    Plaque-associated microgliosis observed by 8 months.

  4. X
    Cognitive Impairment at 31

    Deficits in short-term memory by 8 months in females (data from males unavailable).

Absent
  • Tangles at

    Not observed.

No Data
  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP K670_M671delinsNL (Swedish), PSEN1: deltaE9 APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques, plaque-associated gliosis, cerebral amyloid angiopathy; possible neuron loss in cortex and hippocampal area CA1 in females.

Transgenic mice are hyperactive. Working memory (spontaneous alternation in the Y-maze) is normal at 7 to 8 months, but short-term memory (tested in the Y-maze) is impaired in females (data from males is not available, as wild-type males are unable to perform this test).

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PD-related Research Models

Phenotypes Examined

  • Neuronal Loss
  • Dopamine Deficiency
  • α-synuclein Inclusions
  • Neuroinflammation
  • Mitochondrial Abnormalities
  • Motor Impairment
  • Non-Motor Impairment

When visualized, these phenotypes will distributed over a 18 month timeline demarcated at the following intervals: 3mo, 6mo, 9mo, 1yr, 15mo, 18mo+.

Atp13a2-flox Mouse

Observed
  1. X
    Neuroinflammation at 4

    Germline Atp13a2 KO mice exhibit progressively worsening astrogliosis starting as early as 1 month of age, but in mice with adult-onset Atp13a2 KO in the ventral midbrain, astrogliosis and microglial reactivity were present only transiently after AAV-Cre delivery.

  2. X
    Motor Impairment at 39

    Germline Atp13a2 null mice exhibit some motor defects on the open-field test (starting at 9 months of age) and in the tail suspension test (at 18 months of age), but other motor measures (including balance beam and Rotarod performance) did not differ from wild-type mice.

  3. X
    Neuronal Loss at 52

    No cell loss in the substantia nigra pars compacta (SNpc) in germline Atp13a2 null mice by 18 months of age, but in mice with adult-onset Atp13a2 KO in the ventral midbrain (via AAV-Cre delivery), dopaminergic neuronal degeneration in the SN was observed 10 months after injection (i.e., in 12- to 16-month-old mice).

Absent
  • Dopamine Deficiency at

    No differences observed between germline Atp13a2 null mice and wild-type mice in tyrosine hydroxylase levels (western blot) in the striatum or midbrain at 18 months of age.

  • α-synuclein Inclusions at

    α-synuclein pathology absent in germline KO mice at 18 months of age, and also absent in mice with ventral midbrain, adult-onset Atp13a2 deletion.

No Data
  • Non-Motor Impairment at

    No data.

  • Mitochondrial Abnormalities at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Atp13a2 Atp13a2: Knock-Out Parkinson's Disease

Adult-onset Atp13a2 KO in the ventral midbrain (via AAV-Cre delivery) resulted in neuropathology, including dopaminergic neuronal degeneration in the SN, which was not observed in germline Atp13a2 KO mice.

Motor function partially impaired in germline Atp13a2 KO mice, including defects on the open-field and tail suspension tests, but not on the balance beam or Rotarod.

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DJ-1 KO Rat

Observed
  1. X
    Non-Motor Impairment at 17

    Olfactory detection enhanced (16 mos). Short-term memory abnormal (4.5, 15 mos). Appetitive instrumental learning normal (4, 6, 8 mos). Coping behavior (forced-swim test) impaired (6 mos). No anxiety-like behavior (elevated plus maze; 4, 8, 17 mos), less anxiety on light-dark box (6, 8 mos). No sucrose preference at 9 mos. Sensorimotor function (adhesive removal) unaffected (4, 7, 13 mos).

  2. X
    Motor Impairment at 17

    Abnormalities in gait and strength, vocalizations, and tongue movements were observed. By 4 months, the rats exhibited abnormal paw positioning and a shorter stride. Males showed impaired licking, longer and more frequent ultrasonic vocalizations, and an accelerated decrease in average call intensity with age. Fine motor skills were also impaired in KO versus wild-type rats by 7 months of age.

  3. X
    Mitochondrial Abnormalities at 13

    At 3 months of age, the mitochondrial proteome in DJ-1 KO rats was differentially expressed compared to wild-type rats. Mitochondrial respiration was also increased in KO versus wild-type rats

  4. X
    Neuronal Loss at 26

    Age-related decreases in TH-positive dopaminergic neurons were reported in the substantia nigra and locus coeruleus reaching approximately 50 percent by 8 months of age. No change was found in TH-immunoreactivity in the ventral tegmental area or striatum.

Absent
  • Dopamine Deficiency at

    Striatal dopamine level was increased 2-3 fold in KO rats compared to wild-type levels at 8 months of age. Dopaminergic innervation of the dorsal striatum was intact in DJ-1 KO rats at 4 and 6 months of age compared to wild-type rats. Basal levels of dopamine metabolites and evoked levels of dopamine in the striatum were not different between KO and wild-type rats.

  • α-synuclein Inclusions at

    Staining for α-synuclein revealed no increase in the striatum or in any other brain region assessed.

No Data
  • Neuroinflammation at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Park7 (DJ1) Park7 (DJ1): Knock-Out Parkinson's Disease

Age-related decrease in dopaminergic neurons in the substantia nigra and locus coeruleus; approximately 50 percent reduction by 8 months. Striatal dopamine and serotonin levels elevated 2-3fold over wild-type levels. No change was found in TH-immunoreactivity in the ventral tegmental area or striatum.

Enhanced olfactory detection, abnormal short-term memory, impaired coping behavior, reduced anxiety on light-dark box. Abnormalities in gait, paw positioning, strength, vocalizations, and tongue movements. In males, impaired licking, longer and more frequent ultrasonic vocalizations, and accelerated decrease in average call intensity with age.

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Gba1 D409V KI Mouse (Grabowski)

Observed
  1. X
    Non-Motor Impairment at 17

    Memory is impaired starting at 4 months in homozygous KI mice based on the novel object recognition and contextual fear-conditioning tests. In D409V/null mice, memory was impaired at 9 months; heterozygous KI mice did not exhibit memory deficits at 6 months. Anxiety- and compulsive-like behaviors were perturbed in D409V/null mice at 6 months, based on the marble burying test.

  2. X
    α-synuclein Inclusions at 18

    Progressive α-synuclein accumulation starting at 6 months of age in homozygous and heterozygous KI mice as well as in D409V/null mice, and may be present even as early as 4 months of age, in the forebrain and hippocampus.

  3. X
    Motor Impairment at 14

    Homozygous KI mice do not exhibit gait abnormalities or locomotion based on the open-field test, at 8 and 12 months, respectively. However, D409V/null mice exhibit perturbances in gait as early as 3 months of age.

Absent
  • Neuroinflammation at

    No neuroinflammation observed at 12 months of age in the hippocampus based on GFAP and Iba-1 immunostaining.

  • Neuronal Loss at

    No neurodegeneration in the hippocampus, striatum, or substantia nigra at 12 months of age.

No Data
  • Dopamine Deficiency at

    No data.

  • Mitochondrial Abnormalities at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Gba1 Gba1: Knock-In Parkinson's Disease

No neurodegeneration in the hippocampus, striatum, or substantia nigra at 12 months of age. No neuroinflammation observed at 12 months of age in the hippocampus based on GFAP and Iba-1 immunostaining. Progressive α-synuclein accumulation starting as early as 4 months of age in the forebrain and hippocampus.

Memory impaired starting at 4 months in homozygous KI mice and at 9 months in D409V/null mice. Anxiety- and compulsive-like behaviors perturbed in D409V/null mice at 6 months. Gait and locomotion normal in homozygous KI mice at 8 and 12 months, but impaired gait in D409V/null mice as early as 3 months.

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Gba1 D409V KI Mouse (MJFF)

Observed
  1. X
    Dopamine Deficiency at 55

    Dopamine levels did not differ at 4, 8, and 12 months of age, but dopamine turnover (ratio of DOPAC and HVA to dopamine) tended to increase, though the increase was only significant at 12 months of age.

  2. X
    Non-Motor Impairment at 54

    Cognitive performance was impaired in 12-month-old heterozygous KI mice (but not at 3, 6, or 9 months), based on the Morris water maze and Y-maze. Anxiety-like behavior (based on the open-field test) did not differ at 12 months.

  3. X
    α-synuclein Inclusions at 54

    Homozygous KI mice have higher levels of soluble monomeric α-synuclein in the hippocampus at 12 months than heterozygous KI mice and wild-type controls. Levels of pathologic phosphorylated form pS129 do not differ between homozygous KI mice and controls in the substantia nigra, cortex, or hippocampus.

  4. X
    Neuroinflammation at 54

    Data are mixed on levels of GFAP and Iba-1 immunostaining in KI mice brain. One study in homozygous KI mice found no differences in the striatum and substantia nigra at 4, 8, or 12 months of age; another found decreased GFAP staining in the substantia nigra at 12 months; and a third study (het mice) found increased GFAP and Iba-1 in the hippocampus at 12 months.

  5. X
    Motor Impairment at 36

    Homozygous D409V KI mice generally exhibit motor function similar to wild-type controls (open-field, Rotarod, grip strength, swim velocity). However, a couple of exceptions found in one study were greater grip strength force at 12 months of age and transiently increased locomotor activity on the open-field test at 8 months of age.

Absent
  • Neuronal Loss at

    No differences in the number of dopaminergic neurons in the substantia nigra pars compacta were found between homozygous KI mice and wild-type mice at 4, 8, and 12 months of age.

No Data
  • Mitochondrial Abnormalities at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Gba1 Gba1: Knock-In Parkinson's Disease

No deficits in dopaminergic neuron numbers in the substantia nigra pars compacta between homozygous KI mice and wild-type mice. Dopamine levels did not differ, but dopamine turnover (ratio of DOPAC and HVA to dopamine) tended to increase at older ages. Mixed findings on GFAP and Iba-1 staining across brain regions in KI mice.

Motor function is largely intact in KI mice, apart from transient increases in locomotor activity and increased grip strength at 8 and 12 months, respectively. Cognitive performance was impaired at 12 months of age, but not at younger ages. Anxiety-like behavior was not affected.

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Gba1 L444P KI Mouse (JAX)

Observed
  1. X
    α-synuclein Inclusions at 52

    α-synuclein deposition reported in the striatum of 1-year-old mice in one study, but no differences in α-synuclein levels found in brain extracts of 6- and 14-month-old KI mice in another study.

  2. X
    Neuroinflammation at 53

    Increased GFAP immunoreactivity observed in the striatum of 1-year-old mice in one study, but no differences in striatal GFAP or Iba-1 immunostaining observed in another study of 14-month-old KI mice.

Absent
  • Motor Impairment at

    No deficits in motor balance, as detected by Rotarod and balance beam tests, observed in 16-month-old L444P KI mice.

  • Neuronal Loss at

    No loss in dopaminergic cell numbers in the substantia nigra at 14 months of age.

No Data
  • Dopamine Deficiency at

    No data.

  • Non-Motor Impairment at

    No data.

  • Mitochondrial Abnormalities at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Gba1 Gba1: Knock-In Parkinson's Disease

No loss of dopaminergic cells in the substantia nigra at 14 months. Inconsistent results regarding α-synuclein deposition and striatal GFAP immunostaining.  

No deficits in motor balance, as detected by Rotarod and balance beam tests, observed in 16-month-old L444P KI mice.

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Gba1 L444P KI Mouse (MMRRC)

Observed
  1. X
    Non-Motor Impairment at 13

    Impaired contextual, but not cued, fear conditioning at 3 months of age in heterozygous KI mice. No deficits in olfaction (buried pellet test) or on the novel object recognition test at 24 months of age.

  2. X
    Neuroinflammation at 104

    GFAP  staining was comparable in heterozygous KI and wild-type mice at 8 and 24 months of age. Iba1 staining, however, was increased in 24-month-old heterozygous KI mice, but only in the granule cell layer of the olfactory bulb.

  3. X
    Mitochondrial Abnormalities at 35

    By 8  months of age, heterozygous KI mice have impaired mitochondrial structure (smaller) and function (lower levels of mitochondrial DNA) in the midbrain. Mitochondrial function from cultured cortical neurons also impaired (increased reactive oxygen species generation, decreased mitochondrial complex I enzyme activity, decreased oxygen consumption rate).

Absent
  • Dopamine Deficiency at

    Levels  of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid), HVA (homovanillic acid), or their ratio (to assess dopamine turnover) were similar in saline-treated heterozygous KI and wild-type mice at 8 months of age.

  • α-synuclein Inclusions at

    α-synuclein levels are increased in the ventral midbrain in heterozygous L444P KI mice at 8 months, as well as in other brain regions assessed at 24 months. Another study, however, reported no differences in total synuclein levels at 3 months, but a decrease in soluble phosphorylated α-synuclein. There is no evidence of α-synuclein aggregates in this model.

  • Motor Impairment at

    No differences between heterozygous KI and wild-type mice in open-field test performance at 3 months. At 8 months, heterozygous KI mice also performed at similar levels to wild-type controls on pole and grip strength tests. Heterozygous KI mice may perform better on the pole test at younger (3 months) ages. Pole test performance was also similar between genotypes at 24 months of age.

  • Neuronal Loss at

    No  deficits in the number of TH-positive neurons in the substantia nigra pars compacta or in the density of TH-immunopositive fibers in the striatum in 8-month-old heterozygous L444P KI mice.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Gba1 Gba1: Knock-In Parkinson's Disease

Dopaminergic neuron numbers are intact in the substantia nigra. Some alterations in soluble α-synuclein levels, but no findings of aggregation. Levels of dopamine and its metabolites are not perturbed in heterozygous KI mice. Neuroinflammation as measured by GFAP is not observed in heterozygous KI mice, but Iba1 staining may be increased in some regions.

Largely no differences in motor function between heterozygous KI and wild-type mice from 3 to 24 months of age. Impaired contextual, but not cued, fear conditioning at 3 months of age in heterozygous KI mice, but no deficits in olfaction or on the novel object recognition test at 24 months of age.

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HGBA L444P Tg on Gba1 KO Mouse

Observed
Absent
  • α-synuclein Inclusions at

    Older HGBA L444P /Gba−/− mice do not show evidence of α-synuclein inclusions.

  • Motor Impairment at

    No obvious phenotypic features noted.

  • Neuronal Loss at

    Older HGBA N370S/Gba−/− mice do not show evidence of neuropathology.

No Data
  • Dopamine Deficiency at
  • Non-Motor Impairment at
  • Neuroinflammation at
  • Mitochondrial Abnormalities at
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
GBA1, Gba1 GBA1: Transgenic; Gba1: Knock-Out Parkinson's Disease

Older mice do not show evidence of neuropathology or α-synuclein inclusions. Significant progressive elevations in central nervous system  glucosylsphingosine, but not glucosylceramide, were noted.

No obvious phenotypic features noted.

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HGBA N370S Tg on Gba1 KO Mouse

Observed
Absent
  • α-synuclein Inclusions at

    Older HGBA N370S/Gba−/− mice do not show evidence of α-synuclein inclusions.

  • Motor Impairment at

    No obvious features noted.

  • Neuronal Loss at

    Neuronal Loss Older HGBA N370S/Gba−/− mice do not show evidence of neuropathology.

No Data
  • Dopamine Deficiency at
  • Non-Motor Impairment at
  • Neuroinflammation at
  • Mitochondrial Abnormalities at
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
GBA1, Gba1 GBA1: Transgenic; Gba1: Knock-Out Parkinson's Disease

Older transgenic mice do not show evidence of neuropathology or α-synuclein inclusions. Significant progressive elevations in central nervous system  glucosylsphingosine, but not in glucosylceramide, were noted.

No obvious features noted.

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LRRK2 R1441C KI Mouse

Observed
  1. X
    Non-Motor Impairment at 30

    Acoustic startle reflex equal to wild-type mice at 12 months of age. Intracellular protein transport impaired in primary cultured cells. PKA activity is elevated in the striatum. Ciliation in striatal cholinergic neurons is decreased at 7 months of age and primary cilia formation is perturbed in the somatosensory cortex.

Absent
  • Dopamine Deficiency at

    Basal levels of striatal dopamine, DOPAC, and HVA were comparable between KI and wild-type mice at 3, 12, and 23 months of age. However, evoked dopamine release in the striatum was reduced in adult heterozygous KI mice.

  • α-synuclein Inclusions at

    No abnormal accumulation of α-synuclein observed at 3, 12, and 22 months of age in the substantia nigra pars compacta or locus coeruleus.

  • Neuroinflammation at

    GFAP immunoreactivity was normal at 12 and 22 months of age. However, upon α-synuclein fibril injection, KI mice exhibited increased infiltration of pro-inflammatory monocytes into the brain.

  • Motor Impairment at

    Spontaneous locomotor activity (open-field test) equal to wild-type mice at 3, 12, and 24 months of age. Involuntary motor movement (Rotarod) equal to wild-type mice 3 and 12 months of age.

  • Neuronal Loss at

    No loss of dopaminergic (TH-immunoreactive) neurons in the substantia nigra pars compacta at 12 and 22 months of age. No loss of TH-immunoreactive neurons in the locus coeruleus.

No Data
  • Mitochondrial Abnormalities at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
LRRK2 LRRK2: Knock-In Parkinson's Disease

No loss of dopaminergic (TH+) neurons in the substantia nigra pars compacta at 12 and 22 months. No loss of TH-immunoreactive neurons in the locus coeruleus. Basal levels of striatal dopamine, DOPAC, and HVA were comparable between KI and wild-type mice at 3, 12, and 23 months. However, evoked dopamine release in the striatum was reduced in adult heterozygous KI mice.

Acoustic startle reflex equal to wild-type mice at 12 months of age. Motor learning impaired upon antagonism of dopamine receptors (D1 and D2).

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LRRK2 G2019S KI Mouse

Observed
  1. X
    Non-Motor Impairment at 16

    Altered responses to social-defeat stress (males, 3-4 mos) which correlated with changes in striatal plasticity and intrinsic membrane excitability. Attention deficits, slower information processing, impaired goal-directed learning in 2-6-month-old male KI mice, but cognitive flexibility and novel objective recognition are intact (2-6 mos). Perturbed sleep behavior at 8-10 mos.

  2. X
    Motor Impairment at 81

    A battery of motor tests revealed no baseline deficits at 3-4, 12-13, and 18-19 months of age. However, an increased locomotor response after amphetamine challenge is observed at 18 months. Motor defects are exacerbated following a manganese stressor.

Absent
  • Dopamine Deficiency at

    Striatal dopamine levels do not differ at 2 months of age, and neither do tyrosine hydroxylase levels in the substantia nigra.

  • Neuronal Loss at

    The cytoarchitecture of the neocortex, striatum, hippocampus, and elsewhere is normal in Nissl-stained brain sections of 3-4 month-old mice, and striatal levels of tyrosine hydroxylase are similar to those of controls at P21. In another study, tyrosine hydroxylase levels are reduced in the striatum and midbrain at 2 months of age.

No Data
  • α-synuclein Inclusions at

    No data.

  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
LRRK2 LRRK2: Knock-In Parkinson's Disease

Levels of phospho-substrates of LRRK2 (e.g., Rab10) are increased in the brain. Endocytosis and axonal transport defects in neurons. Cholinergic innervation density is lower in the prelimbic/infralimbic cortical areas and dorsomedial striatum, but not in the dorsal lateral geniculate nucleus in 2-6-month-old males. Microglial immunostaining is similar in the striatum and midbrain at 8 weeks

Attention deficits, slower information processing speeds, and impaired goal-directed learning are evident in 2-6-month-old mice—deficits rescued by systemic administration of the acetylcholinesterase inhibitor donepezil. Cognitive flexibility and novel objective recognition similar to controls. Sleep behavior is perturbed at 8-10 months of age.

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LRRK2 G2019S Mouse (BAC Tg)

Observed
  1. X
    Dopamine Deficiency at 52

    Age-related decline in striatal dopamine content. Levels were decreased at 12 months of age, but not significantly different from controls at 6 months of age. Also, decreased dopamine metabolite homovanillic acid (HVA).

  2. X
    Non-Motor Impairment at 26

    Tg mice spend less time in the REM sleep phase at 12 and 18 months of age. Age-dependent increase in plasma corticosterone (present starting at 6-8 months of age). Nuclear envelope integrity is perturbed in dopaminergic neurons at 12 months.

  3. X
    Neuroinflammation at 8

    Application of α-synuclein fibrils leads to exacerbated responses (more inclusions and greater infiltration of pro-inflammatory monocytes).

  4. X
    Motor Impairment at 78

    Behavior in hemizygous mice was comparable to littermate controls in terms of activity levels (open-field test) and coordination (beam-walk test) at 6 and 12 months, , but not at 18 months of age, when Tg mice develop motor deficits (Rotarod).

  5. X
    Mitochondrial Abnormalities at 0

    Primary cultured cells from Tg mice exhibit mitochondrial fragmentation and membrane depolarization.

Absent
  • α-synuclein Inclusions at

    No evidence of α-synuclein inclusions up to 18 months of age. However, there is mixed evidence on whether cultured mutant hippocampal neurons have increased levels of α-synuclein protein. After exposure to exogenous α-synuclein fibrils, mutant neurons developed more α-synuclein inclusions than non-Tg neurons.

  • Neuronal Loss at

    No evidence of neuronal or other cell death in any brain region, including the cortex, striatum, and hippocampus. There was no difference in the number of dopaminergic neurons in the substantia nigra compared to littermate controls at 6 or 12 months.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
LRRK2 LRRK2 G2019S LRRK2: Transgenic Parkinson's Disease

Brain appears normal. No neuronal or cell death at 12 months. Impaired neurite motility and synaptic vesicle endocytosis in cultured neurons. No increase in α-synuclein or ubiquitin levels or aggregation; however, cultured neurons developed more inclusions when exposed to exogenous α-synuclein fibrils. Decreased striatal dopamine content, decreased evoked release.

Apparently normal behavior. No change in activity level or motor coordination at 12 months. Motor deficits appear at 18 months.

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LRRK2 G2019S Mouse (Tg)

Observed
  1. X
    Non-Motor Impairment at 45

    Anxiety/depression-like symptoms were observed at 10-12 months of age.

  2. X
    α-synuclein Inclusions at 52

    Around 2 years of age, mice did not exhibit abnormalities in α-synuclein in the ventral midbrain, striatum, or cerebral cortex. However, one study found α-synuclein accumulation in whole brain lysates of 12- to 19-month-old transgenic mice.

  3. X
    Neuroinflammation at 63

    Around 2 years of age, mice did not have GFAP abnormalities in the ventral midbrain, striatum, or cerebral cortex. However, activated microglia were reported in the striatum at 14 months, and CD68 and TNF-α levels were increased in whole brains at 4-6 months. Others have not observed differences in Iba-1 staining (microglial marker) at 6, 12, or 18 months in the striatum or substantia nigra.

  4. X
    Motor Impairment at 35

    Rotarod performance deteriorated in 14- to 18-month-old mice, but minor deficits are already observed as early as 8 months of age. Muscle weakness observed on the hanging wire test by 8 months of age. No change in pre-pulse inhibition of the acoustic startle reflex.

  5. X
    Mitochondrial Abnormalities at 63

    Increased numbers and condensation of mitochondria in striatal microglia were reported at 14 months. Abnormally high levels of condensed mitochondria were also observed in cortical and striatal neurons at 17-18 months.

  6. X
    Neuronal Loss at 83

    By 19-21 months, mice lose 18 percent of TH-positive dopaminergic neurons in the substantia nigra pars compacta and 14 percent of dopaminergic dendrites in the substantia nigra pars reticulata. At 1-2 months neuronal numbers were normal. Some authors do not see differences in TH staining up to 2 years of age. No abnormal neuronal loss is observed in the ventral tegmental area or cerebellum.

Absent
  • Dopamine Deficiency at

    At 14-15 months of age, hemizygous mice had normal levels of striatal dopamine, DOPAC, and HVA. However, in the olfactory bulb, levels of HVA and DOPAC were lower, but dopamine was unchanged.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
LRRK2 LRRK2 G2019S LRRK2: Transgenic Parkinson's Disease

Age-dependent dopaminergic neuron degeneration in the substantia nigra, though reports are mixed. No reduction in striatal dopaminergic terminals or dopamine levels. Some reports of α-synuclein accumulation. Abnormal mitochondria in striatal neurons and microglia; accumulation of autophagic vacuoles. Evidence for activated striatal microglia and increased levels of CD68 and TNF-α in whole brain.

Deterioration of Rotarod performance in 14- to 18-month-old mice. Muscle weakness observed on the hanging wire test by 8 months of age. No change in pre-pulse inhibition of the acoustic startle reflex. Anxiety/depression-like symptoms at 10-12 months.

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LRRK2 G2019S Rat (BAC Tg)

Observed
  1. X
    Non-Motor Impairment at 26

    Bone marrow myeloid progenitor numbers were decreased, but suppressive myeloid cells were increased at 6 to 11 months of age

  2. X
    Motor Impairment at 35

    Mild abnormalities in motor behavior. Slightly more postural instability at 8 months of age (but not at 4 and 12 months). Slightly more rearing events at 12 months, but not at younger ages.

Absent
  • Dopamine Deficiency at

    No change in striatal dopamine levels. No change in 3,4-dihydroxyphenylacetic acid (DOPAC) levels. No change in the rate of dopamine turnover. At 12 months of age Tg rats exhibited higher levels of striatal homovanillic acid (HVA).

  • α-synuclein Inclusions at

    Under basal conditions no α-synuclein inclusions were observed. 

  • Neuroinflammation at

    No increase in Iba-1 positive microglia or GFAP-positive astrocytes in the substantia nigra at 12 months of age. However, iNOS expression was elevated in nigral dopaminergic neurons.

  • Neuronal Loss at

    No overt loss of dopaminergic neurons in the substantia nigra out to 12 months of age.

No Data
  • Mitochondrial Abnormalities at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
LRRK2 LRRK2 G2019S LRRK2: Transgenic Parkinson's Disease

No overt neurodegeneration out to 12 months of age. Elongated dopaminergic neurons. Elevated oxidative and nitrosative stress. No evidence of gliosis. No α-synuclein inclusions until challenged with exogenous α-synuclein. No change in dopamine levels.

Mild abnormalities in motor behavior. Slightly more postural instability at 8 months of age (but not at 4 and 12 months). Slightly more rearing events at 12 months, but not at younger ages.

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Lrrk2 KO Mouse

Observed
  1. X
    Neuroinflammation at 87

    Striatal staining of GFAP, a marker of reactive astrocytosis, did not differ between control and KO mice, but cells positive for Iba1 staining, a marker of activated microglia, were moderately enlarged in the striatum of 20 -month-old KO mice. Cx3cr1 mRNA levels higher in KO mouse brains.

  2. X
    Motor Impairment at 52

    Motor behavior is generally intact up to 18 months based on Rotarod and open field tests. However, some age-dependent effects are observed on the open field test: 12 -month-old mice traveled longer distances and had higher walking speeds versus controls, which was not apparent in 3- or 24-month-old mice. Older (24 months) mice had deficits in motor skill learning as measured by Rotarod.

  3. X
    Mitochondrial Abnormalities at 9

    Adult (9 - to 23-week-old) Lrrk2 KO mice exhibit enhanced mitophagy in dopaminergic neurons of the substantia nigra pars compacta, as detected by an increase in the number of mitolysosomes.

Absent
  • Dopamine Deficiency at

    Levels  of TH in the striatum are equal between genotypes in 18- to 24-month-old mice.

  • Non-Motor Impairment at

    No differences were observed between KO and wild-type mice across 6 to 24 months of age on several behavioral tests, including the elevated plus maze for anxiety-like behavior, the buried treat test to measure hyposmia, the grip strength test for forelimb strength, or working memory as measured by spontaneous alternation.

  • α-synuclein Inclusions at

    No abnormal accumulation of α-synuclein in the cell bodies of striatal neurons observed in 20-month-old KO mice.

  • Neuronal Loss at

    Neuronal Loss No  differences between KO and wild-type mice up to 24 months of age in the number of tyrosine hydroxylase (TH)–positive cells in the substantia nigra pars compacta. No neurodegeneration markers observed in the striatum and cortex at 20 months. Cerebral cortex and dorsal (but not ventral) striatum volumes reduced at 12 months.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Lrrk2 Lrrk2: Knock-Out Parkinson's Disease

No loss in the number of TH–positive cells in the substantia nigra pars compacta up to 24 months. Cerebral cortex and dorsal striatum volumes reduced at 12 months. Striatal spiny projection neurons were enlarged and the frequency of nuclear invaginations was increased at 12 months, suggesting premature aging. Dendritic morphology perturbed at 12 months.

No differences between KO and wild-type mice up to 24 months on several behavioral tests, including the elevated plus maze for anxiety-like behavior, the buried treat test to measure hyposmia, the grip strength test for forelimb strength, or working memory as measured by spontaneous alternation. Older (24-month-old) mice showed deficits in motor skill learning as measured by Rotarod.

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Lrrk2 KO Rat

Observed
  1. X
    Non-Motor Impairment at 5

    Abnormalities occur in peripheral organs, most notably the kidney, but also the liver, lung, and spleen. Changes are progressive, although they do not appear to shorten lifespan. The earliest reported alterations occur in the kidneys at 1 month of age.

Absent
  • Dopamine Deficiency at

    Basal levels of dopamine metabolites (3,4-dihydroxyphenylacetic and homovanillic acid) do not differ between Lrrk2 KO and wild-type rats at 4, 8, and 12 months of age. Evoked release of dopamine also does not differ between KO and wild-type rats.

  • Neuroinflammation at

    When challenged with LPS or α-synuclein overexpression, Lrrk2 KO rats show lower levels of pro-inflammatory CD68-positive myeloid cells in the substantia nigra than wild-type rats.

  • Motor Impairment at

    Assessment of Rotarod performance revealed no impairment at 12 months of age compared with wild-type rats.

  • Neuronal Loss at

    Under basal conditions, the number of TH-positive cells in the substantia nigra is comparable between Lrrk2 KO and wild-type rats. When challenged with LPS or α-synuclein overexpression, Lrrk2 KO rats develop significantly less neurodegeneration in the substantia nigra than wild-type rats.

No Data
  • α-synuclein Inclusions at

    No data.

  • Mitochondrial Abnormalities at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Lrrk2 Lrrk2: Knock-Out Parkinson's Disease

Not observed. Protection against dopaminergic cell loss under conditions involving LPS or α-synuclein overexpression in the substantia nigra. No changes in basal or evoked release of dopamine.

One assessment of Rotarod performance revealed no impairment at 12 months of age compared with wild-type rats.

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LRRK2 R1441C Mouse (Tg - Conditional)

Observed
Absent
  • Dopamine Deficiency at

    HPLC analysis of striata from 10-month-old mice revealed no significant differences in the levels of dopamine or its metabolites DOPAC and HVA.

  • Non-Motor Impairment at

    Olfactory function, as assessed by the ability to locate buried food, was normal out to 20 months of age.

  • α-synuclein Inclusions at

    Immunohistochemical analysis of the brain at 22 months did not reveal abnormalities in α-synuclein, and no proteinaceous inclusions were seen.

  • Neuroinflammation at

    Immunohistochemical analysis of the brain at 22 months found GFAP and Iba1 immunoreactivity comparable to control levels.

  • Motor Impairment at

    Around 20 months of age, R26-LRRK2 mice behaved normally, exhibiting no deficits in locomotor activity (open-field test), motor coordination (Rotarod), or gait (digital CatWalk system).

  • Neuronal Loss at

    In the substantia nigra pars compacta, there was no difference in the number of TH-positive neurons or the total number of Nissl-positive neurons at 12 and 22 months.

No Data
  • Mitochondrial Abnormalities at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
LRRK2 LRRK2 R1441C LRRK2: Transgenic Parkinson's Disease

No neurodegeneration in the brain. No proteinaceous inclusions of α-synuclein, ubiquitin, or tau. No reactive gliosis. No change in dopamine levels. Subtle morphological abnormalities in dopaminergic and non-dopaminergic neuronal nuclei, including altered nuclear envelope.

No overt behavioral differences. Activity levels and Rotarod performance are normal into advanced age.

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LRRK2 WT Mouse (BAC Tg)

Observed
  1. X
    Dopamine Deficiency at 52

    Striatal dopamine levels, as measured by PET imaging with [18F]FDOPA uptake, are higher in WT-OX versus non-Tg mice.

  2. X
    Motor Impairment at 52

    WT-OX mice (12 months) are hyperactive on several parameters of the open-field test. Gait analysis (Cat-Walk system) was also perturbed relative to non-Tg controls. However, the number of rears did not differ.

Absent
  • Mitochondrial Abnormalities at

    Mitochondrial morphology and levels of proteins involved in mitochondrial fission (Drp1 and Fis1) are normal at 12 months of age.

No Data
  • Non-Motor Impairment at

    No data.

  • α-synuclein Inclusions at

    No in vivo data, but α-syn colocalization with LAMP-2 is increased in cultured neurons from WT-OX mice.

  • Neuroinflammation at

    No data.

  • Neuronal Loss at

    No data on neuron numbers are available, but neurite length is reduced in primary hippocampal neurons and primary nigral tyrosine hydroxylase-positive neurons of WT-OX mice versus non-Tg mice.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
LRRK2 LRRK2: Transgenic Parkinson's Disease

Overtly normal brain structure. Intact, but shorter, neurites.

Motor hyperactivity at 12 months of age.

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MCI-Park Mouse

Observed
  1. X
    Dopamine Deficiency at 5

    Profound loss of evoked dopamine release in the dorsolateral striatum as early as 30 days. In contrast, somatodendritic dopamine release in the SN did not differ between genotypes at 30 days, but was dramatically reduced by 60 days.

  2. X
    Non-Motor Impairment at 2

    Impaired associative learning (Y-maze test) at 30 days . Impaired sleep functions starting at 6 weeks of age, with significantly altered sleep-wake patterns (total, NREM, and REM sleep), increased sleep fragmentation, and altered EEG activity.

  3. X
    Motor Impairment at 6

    Striatal motor learning (adhesive removal test) was impaired starting at 30 days. Rearing in the cylinder testing was impaired at 40 days. Total distance travelled was decreased by 60 days on the open-field test. By 100 days, splayed hindlimbs, abnormal paw placement, and alterations in stride observed.

  4. X
    Mitochondrial Abnormalities at 3

    By 20 days mitochondria were in an oxidative phosphorylation deficit. Altered mitochondria structure, but not mitochondrial density, was observed at 35 days in dopaminergic neurons of the SN. Metabolic reprogramming to a glycolytic-predominant state of mitochondria was indicated by alterations in expression of genes and functional pharmacologic experiments.

  5. X
    Neuronal Loss at 4

    TH expression decreased at 30 days in the dorsal striatum. By age 60 days, TH expression decreased in substantia nigra dopaminergic neurons. No neurodegeneration was observed in axons, cell bodies, or dendritic arbors of SN dopaminergic neurons at 60 days. By 120 to 150 days, neurodegeneration is present and about 40% of SN dopaminergic neurons are lost.

Absent
No Data
  • α-synuclein Inclusions at

    No data.

  • Neuroinflammation at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Conditional Knock-out Parkinson's Disease

Progressive reductions in TH expression in the striatum and SN. Overt neuron loss in the SN only at older ages (>120 days). Electrophysiological measurement of SN dopaminergic neurons showed altered pacemaking activity and burst spiking. Altered expression of many neuronal genes. Loss of evoked dopamine release in the dorsolateral striatum at 30 days of age.

Impaired associative learning and striatal motor learning at 30 days. Impaired rearing at 40 days. Decreased total distance travelled by 60 days. By 100 days, splayed hindlimbs, abnormal paw placement, and alterations in stride. Impaired sleep functions starting at 6 weeks.

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Parkin KO Mouse

Observed
  1. X
    Dopamine Deficiency at 11

    Levels of striatal dopamine and metabolites DOPAC and HVA were normal at 6, 12, 18, and 24 months. In another study, striatal extracellular dopamine was increased, as measured by no-net-flux microdialysis, in 8-9-month-old mice. In a third study, evoked striatal dopamine release was reduced in striatal slices of 2-4-month-old mice.

  2. X
    Non-Motor Impairment at 9

    Novel object recognition was decreased at 4-5 months of age and reduced sociability, increased repetitive behaviors, and deficits in communication were present at 2-3 months of age. Outcomes from the forced swim test, time spent investigating novel odors, latency to find buried food, the Barnes maze test, hot plate test, Morris water maze appear unaffected. 

  3. X
    Motor Impairment at 19

    On the beam traversal task, KO mice displayed deficits starting at 2-4 months of age. General behavior (beam breaks) on the open-field test did not differ at 6, 12, and 18 months of age. Findings on the Rotarod suggest no differences or that KO mice may have enhanced performance. 

  4. X
    Mitochondrial Abnormalities at 7

    Mitochondrial defects begin at 7 weeks. Proteomic analyses reveal differences in ventral midbrain lysates of proteins involved in mitochondrial function. Respiratory and antioxidant capacity, mitophagy, and mitochondrial DNA are affected. Mitochondrial structure appears intact in the brain, but is affected in heart tissue.

Absent
  • α-synuclein Inclusions at

    Inclusions of α-synuclein were not observed in any brain region.

  • Neuroinflammation at

    Spinal cord staining of GFAP did not differ between non-transgenic and parkin KO mice at 130 days of age.

  • Neuronal Loss at

    In the substantia nigra, the number of dopaminergic neurons (as detected by TH staining) did not differ between parkin KO and wild-type mice up to 24 months. Dopaminergic projections in the striatum were also normal.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Park2 Park2: Knock-Out Parkinson's Disease

No loss of dopaminergic neurons in the substantia nigra. Striatal dopamine levels may be increased basally, but reduced when evoked. Striatal medium spiny neurons had reduced synaptic excitability at 6–9 months and impaired LTP and LTD at 8 weeks, but other passive and active membrane properties were unaffected. No α-synuclein inclusions or astrogliosis.

Outcomes from the forced swim test, time spent investigating novel odors, latency to find buried food, the Barnes maze test, hot plate test, Morris water maze appeared unaffected. In contrast, novel object recognition was decreased at 4-5 months and reduced sociability, increased repetitive behaviors, and deficits in communication were present at 2-3 months.

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Parkin KO Rat

Observed
  1. X
    Non-Motor Impairment at 9

    Orientation to an olfactory stimulus was normal. At 2 months of age, male KO rats had a greater preference for methamphetamine than wild-type rats based on self-administration and place preference tests.

  2. X
    Mitochondrial Abnormalities at 14

    Alterations in mitochondrial protein expression in synaptic and nonsynaptic striatal samples of 3-month-old KO rats.

  3. X
    Neuronal Loss at 35

    A small, non-significant reduction in dopaminergic neurons was observed in the substantia nigra at 8 months of age.

Absent
  • Dopamine Deficiency at

    No differences in striatal dopamine levels at 4, 6, or 8 months. Altered dopaminergic transmission factors in the striata, including MAO, β-phenylethylamine, trace amine-associated receptor 1, and postsynaptic dopamine D2 receptors in 2-month-old KO rats. Striatal dopamine metabolite levels decreased with age in KO rats, showing lower levels at 12 months than at 8 months.

  • α-synuclein Inclusions at

    There was no increase in α-synuclein protein in the striatum or any other brain region assessed.

  • Motor Impairment at

    No behavioral deficits were detected at 4, 6, and 8 months of age. Motor functioning, including performance on the Rotarod, was intact. However, at 2 months, male KO rats made fewer small stereotypic movements, such as scratching and grooming, than wild-type controls.

No Data
  • Neuroinflammation at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Park2 Park2: Knock-Out Parkinson's Disease

No significant changes in dopaminergic neurons in the substantia nigra nor striatal dopamine levels, but alterations in dopaminergic signaling were detected at an early age, as were disruptions in mitochondrial protein expression in striatum. No increase in α-synuclein. Evoked release of striatal glycine greater at 12 months versus wild-type rats.

No behavioral deficits detected at 4, 6, and 8 months of age. However, at 2 months, male KO rats made fewer small stereotypic movements, such as scratching and grooming, than wild-type controls. At 2 months, male KO rats had a greater preference for methamphetamine than wild-type rats.

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Parkin Q311X Mouse (BAC Tg)

Observed
  1. X
    Dopamine Deficiency at 69

    Surviving nigral neurons at 16 months of age had reduced tyrosine hydroxylase expression. By 19-21 months, striatal concentrations of dopamine and the dopamine metabolite DOPAC were decreased compared with non-Tg littermates.

  2. X
    Non-Motor Impairment at 68

    Autophagy and lysosomal dysfunction in mutant mice at 16-17 months of age.

  3. X
    Non-Motor Impairment at 71

    Autophagy and lysosomal dysfunction in mutant mice at 16-17 months of age.

  4. X
    α-synuclein Inclusions at 72

    Lewy body-like inclusions were not observed at any age, however, mutant mice exhibit age-dependent accumulation of proteinase-K resistant endogenous α-synuclein in the substantia nigra at 16 months of age.

  5. X
    Motor Impairment at 70

    Behavior was fairly normal at 3 months, but motor abnormalities were detected by 16 months of age, including hypoactivity and deficits in coordination and in motor response to sensory stimuli.

  6. X
    Mitochondrial Abnormalities at 4

    Mitochondrial dysfunction observed as early as 1 month of age, based on electron microscopy (e.g., lacking an outer membrane, swollen) and expression of the short isoform of OPA1.

  7. X
    Neuronal Loss at 26

    Progressive loss of dopaminergic neurons in the substantia nigra, starting as early as 6 months of age. About 40 percent loss by 16 months of age with a corresponding decrease in dopaminergic projections to the striatum. Neurons in the ventral tegmental area were relatively spared.

Absent
No Data
  • Neuroinflammation at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Park2 Parkin Q311X Park2: Transgenic Parkinson's Disease

Degeneration of dopaminergic neurons in the SN and nerve terminals in the striatum. Reduced dopamine in the striatum. Accumulation of proteinase-K resistant α-synuclein and oxidative protein damage. Dysfunction in the burst-firing pattern activity of dopaminergic SN neurons and increased expression of markers for excitotoxic damage.

Late-onset hypoactivity (about 16 months of age), other modest changes in motor behavior and coordination in tests that included traversing a beam or removing adhesive.

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Parkin S65A KI Mouse

Observed
  1. X
    Motor Impairment at 53

    Impaired performance on the raised balance beam at 12  and 18 months of age in homozygous KI mice. No deficits in Rotarod performance or gait analysis.

  2. X
    Mitochondrial Abnormalities at 52

    Mitochondrial respiration (respiratory control ratio) was impaired in an age-dependent manner—at 12  months, but not at 3 months—in homozygous KI mice. No deficits in basal mitophagy.

Absent
  • Dopamine Deficiency at

    No differences in levels of striatal dopamine and 3,4-DOPAC, nor in their ratio, between 18-month-old homozygous KI mice and wild-type mice.

  • Neuroinflammation at

    Immunolabeling of astrocytes (GFAP) and microglia (Iba1) did not differ between homozygous Parkin KI mice and wild-type mice.

  • Neuronal Loss at

    No deficits in striatal anatomy or volume or in nigrostriatal innervation in 18-month-old homozygous KI mice.

No Data
  • Non-Motor Impairment at

    No data.

  • α-synuclein Inclusions at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Park2 Park2 S65A Park2: Knock-In Parkinson's Disease

No evidence of nigrostriatal neuropathology in 18-month-old homozygous mice.

Motor dysfunction on the raised balance beam by 12 months of age. No deficits in Rotarod performance or gait.

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PINK1 G309D (PINK1-/-) Mouse (KI)

Observed
  1. X
    Dopamine Deficiency at 39

    Decreased dopamine concentration in the striatum by 9 months of age.

  2. X
    Neuroinflammation at 81

    Expression of factors involved in Toll-like receptor signaling were increased in the cerebellum, as were astrocytic and microglial markers in the corticospinal tract and striatum at 18 months.

  3. X
    Motor Impairment at 70

    At 16 months of age Pink1-/- mice exhibited decreased spontaneous locomotor activity. Strength and coordination were intact.

  4. X
    Mitochondrial Abnormalities at 13

    By 3 months of age the mice exhibited a mitochondrial import defect. This phenotype was more severe at 6 months and import was reduced nearly 50% by 12 months of age. By 6 months, ATP production, respiration, and mitochondrial membrane potential were also reduced.

Absent
  • Non-Motor Impairment at

    Mutant mice performed similarly to wild-type mice in tests assessing the startle reflex, sweating, and anxiety.

  • α-synuclein Inclusions at

    No Lewy body-like inclusions or α-synuclein aggregates in the brainstem or substantia nigra, but expression levels of α-synuclein are altered in brainstem/midbrain.

  • Neuronal Loss at

    Neuronal loss was not observed at 18 months of age (total neuronal population and TH-positive subset).

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
PINK1 Pink1 G309D PINK1: Knock-In Parkinson's Disease

No neuronal loss. No Lewy bodies or α-synuclein aggregates, but α-synuclein expression change in brainstem/midbrain. Low dopamine levels. Mitochondrial dysfunction (e.g., reduced ATP, reduced respiratory activity). Increase in factors involved in Toll-like receptor signaling in the cerebellum, and increased astrocytic and microglial markers in the corticospinal tract and striatum.

Reduced spontaneous locomotor activity in open-field test. No difference in strength or coordination.

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PINK1 KO Mouse

Observed
  1. X
    Non-Motor Impairment at 0

    Modest vocalization deficits observed at 4-6 months. Reduced BDNF levels in the midbrain and cortex at 10 months. Cardiac hypertrophy observed at 2 and 6 months of age.

  2. X
    Motor Impairment at 23

    Reduced spontaneous locomotor activity and skill reported at 3-6 months.

  3. X
    Mitochondrial Abnormalities at 9

    Altered shape, density, and movement of dendritic mitochondria observed in cultured primary neurons from embryonic mice. Also, an abnormal rise in serum cytokines  in response to acute mitochondrial stress was reported in vivo. By 2 months of age, mitochondrial dysfunction observed in cardiomyocytes.

Absent
  • Dopamine Deficiency at

    Overall striatal levels of dopamine did not significantly differ from levels in wild-type mice at 2-3 months or 8-9 months of age.

  • Neuronal Loss at

    No decrease in the number of dopaminergic neurons in the substantia nigra at 2-3 months or 8-9 months of age. Neuronal morphology also grossly intact.

No Data
  • α-synuclein Inclusions at

    No data.

  • Neuroinflammation at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Pink1 Pink1: Knock-Out Parkinson's Disease

Normal numbers of dopaminergic neurons and tyrosine hydroxylase levels in substantia nigra at 8-9 months of age. Alterations in the dendrites of midbrain dopaminergic neurons and cultured cortical neurons. Altered shape, density, and movement of dendritic mitochondria in cultured primary neurons from embryonic mice. Reduced BDNF levels in the midbrain and cortex at 10 months.

Reduced spontaneous locomotor activity and skill at 3-6 months. Modest vocalization deficits at 4-6 months.

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Pink1 KO Rat

Observed
  1. X
    Non-Motor Impairment at 9

    Nociception alterations in male KO rats observed at 6 to 10 months of age, indicating thermal hyperalgesia. This effect was present in female KO rats at 2 months of age, but not at older ages. Abnormalities in ventilation frequency were also observed in male KO rats. Defects in ultrasonic vocalizations starting at 2 months of age in male and female KO rats.

  2. X
    α-synuclein Inclusions at 18

    Alpha-synuclein aggregates were found as early as 4 months of age and increased in number up to 12 months. Areas affected include the periaqueductal gray, substantia nigra pars compacta, locus coeruleus, nucleus ambiguous, cortex, thalamus, and striatum.

  3. X
    Motor Impairment at 5

    Abnormalities in gait, coordination, and strength. By 5 weeks, KOs had increased foot slips on the tapered balance beam, at 7 weeks they showed hind limb fatigue, which progressed to hind limb dragging, and by 2 months they exhibited alterations in oromotor behaviors. Deficits in gait may be transient. Partial reversal of motor impairment by Levodopa.

  4. X
    Mitochondrial Abnormalities at 18

    Alterations in mitochondrial metabolites and mitochondrial protein expression were reported as early as 4 months of age in cortex and striatum. Oxygen consumption rates were elevated in striatal mitochondria isolated from 9-month-old rats, but not in non-synaptic samples from 3-month-old rats.

  5. X
    Neuronal Loss at 11

    Age-related decrease in tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra. A reduction of 25 and 50 percent at 6 months and 8 months, respectively. Deficits in TH staining in the substantia nigra have been observed as early as at 2.5 months of age. While some studies did not see any changes in TH-positive cells in the striatum, others have observed a 15% loss.

Absent
  • Dopamine Deficiency at

    One study found striatal dopamine levels were increased two- to threefold in Pink1 KO rats compared with wild-type levels at 8 months of age, whereas another reported a slight decrease at this age. In the dorsal striatum, KO rats have age-dependent differences in basal and evoked dopamine levels, but no differences were observed compared to wild-type rats.

No Data
  • Neuroinflammation at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Pink1 Pink1: Knock-Out Parkinson's Disease

Age-related decrease in dopaminergic neurons in the substantia nigra; greater than 50 percent reduction at eight months. Alterations in striatal dopamine and serotonin levels. Progressive increase in α-synuclein aggregates and reduced brain volume across numerous regions. Increased ventricular volume. Alterations in cortical and striatal mitochondria.

Abnormalities in gait, coordination, and strength. As early as 5 weeks of age, KOs had increased foot slips on the tapered balance beam, at 7 weeks they showed hind limb fatigue, which progressed to hind limb dragging, and by 2 months they exhibited alterations in oromotor (lingual) behaviors.

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Thy1-αSyn “Line 61” Mouse

Observed
  1. X
    Dopamine Deficiency at 63

    Line 61 mice lose striatal dopamine progressively, starting at about 14 months of age. Between approximately 6 and 10 months, however, the neurotransmitter’s extracellular levels are transiently increased.

  2. X
    Non-Motor Impairment at 11

    Disruptions in olfaction, circadian rhythms, sleep, cognition, social behavior, and autonomic function have been reported. Several are reminiscent of PD non-motor impairments. Alterations in olfaction, circadian rhythms, and the autonomic regulation of heartrate occur as early as 3 months of age.

  3. X
    α-synuclein Inclusions at 4

    Proteinase K-resistant aggregates are seen at 1 month and increase with age, including the substantia nigra, periqueductal gray, cortex, striatum, vagus, olfactory bulb, thalamus, locus coeruleus, and cerebellum, as well as cholinergic neurons in the colon. Elevated levels of phospho-serine 129 α-synuclein are found in the substantia nigra, striatum, cortex, frontal cortex, and hippocampus.

  4. X
    Neuroinflammation at 5

    Neuroinflammation markers have been seen in the cortex, striatum, substantia nigra, and hippocampus. The time course and profile vary between brain regions and some features remain subject to debate. However, neuroinflammation appears to affect the striatum first (1 month), and then the substantia nigra (5–6 months). At older ages, particularly in the substantia nigra, inflammation attenuates.

  5. X
    Motor Impairment at 4

    Impairments in balance, coordination, muscle strength, fine motor skills, vocalizations, and stress-induced defecation arise between 1 and 3 months. Transient hyperactivity is seen between 4 and 9 months of age, followed by hypoactivity and sensorimotor deficits at about 15 months. As the phenotype becomes more severe, the mice develop difficulty eating, akinesia, and hunched posture.

  6. X
    Mitochondrial Abnormalities at 18

    The functions of mitochondrial respiratory complexes in midbrain and striatum are impaired, with the earliest reported deficit affecting complex I in the midbrain at 4 months. Elevated α-synuclein accumulation was found in mitochondria of the midbrain, striatum, and cortex.

  7. X
    Neuronal Loss at 16

    Although neuron loss occurs in the neocortex and hippocampal CA3 region as early as 3–4 months of age, there is no reduction in the PD-relevant dopaminergic neurons of the substantia nigra, even at 22 months of age.

Absent
No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
SNCA SNCA: Transgenic Parkinson's Disease

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Vps35 p.D620N KI Mouse

Observed
  1. X
    Dopamine Deficiency at 13

    Enhanced peak amplitude in dopamine release and prolonged reuptake kinetics in acute striatal slices from 3-month-old mice; decreased DAT and increased VMAT2. Basal levels of dopamine and metabolites in dorsolateral striatum did not differ, but the DOPAC+HVA/DA ratio was increased. At 16 months, dopamine in striatal homogenates was reduced, but levels of metabolites (DOPAC, HVA) did not differ.

  2. X
    α-synuclein Inclusions at 65

    No differences in α-synuclein puncta density or distribution in the SNpc at 3 months. No pathological α-synuclein observations seen throughout the brain at 13 months. However, at 15 to 16 months, increased somatic α-synuclein immunoreactivity found in the SNpc, and increased α-synuclein oligomers and aggregated α-synuclein observed in the ventral midbrain.

  3. X
    Neuroinflammation at 64

    Increased GFAP immunostaining in the SNpc, but not in the striatum, of 15- to 16-month-old VKI mice; no GFAP differences observed at earlier ages. No differences in microgliosis (Iba-1 immunostaining) in the SNpc or the striatum up to 16 months of age.

  4. X
    Motor Impairment at 60

    Motor deficiencies on the open-field test and the beam walking test appear at 14 months of age, but not earlier from 3 to even 13 months of age. However, performance on other motor tests—Rotarod and grip strength—did not differ at the advanced age (14 months). No deficits seen in the cylinder test (rearing) at 3 months. Amphetamine-induced hyperlocomotion is rescued by LRRK2 kinase inhibition.

  5. X
    Mitochondrial Abnormalities at 61

    Mitochondrial structure, assesed by EM, was perturbed at 14 months, but not at 3 months, of age. Mitochondrial function—namely, the oxygen consumption rate—was reduced in older (15-month-old) mice.

  6. X
    Neuronal Loss at 56

    Loss of TH-positive neurons in the SNpc and loss of TH-positive nerve terminals in the striatum at 13-16 months. Widespread axonal degeneration in the brain at 13 months.

Absent
  • Non-Motor Impairment at

    No deficits in the buried pellet test, measuring olfactory function, from 6 to 14 months of age. No defects in gastrointestinal function (as measured by stool frequency and water content) up to 14 months of age.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Vps35 Vps35: Knock-In Parkinson's Disease

Loss of TH+ neurons in SNpc and TH+ terminals in striatum at 13-16 mos. Widespread axonal degeneration at 13 mos. Increased somatic α-synuclein in SNpc; α-synuclein oligomers and aggregates in ventral midbrain at 15-16 mos. Increased somatodendritic tau/p-tau with age, but no neurofibrillary pathology. Increased GFAP in SNpc, but not striatum at 15-16 mos. No microgliosis up to 16 mos.

No deficits in the buried pellet test, measuring olfactory function, from 6-14 months. Deficits in mood (anxiety/apathy) and/or cognition on elevated plus maze, starting at 3 months (unpublished).

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α-synuclein A30P/A53T Mouse (Tg)

Observed
  1. X
    Dopamine Deficiency at 9

    Striatal dopamine concentrations were lower at all ages tested, including the earliest age, 2-3 months. Dopamine concentrations dropped with age, and levels of metabolites (e.g., DOPAC and HVA) were also lower in HM2 mice than non-Tg by 13-23 months of age.

  2. X
    Motor Impairment at 30

    At young age 2-3 months, HM2 mice were more active than non-Tg controls, but by middle age (7-9 months) they were less active. At advanced ages (13-23 months), they also exhibited impaired coordination as measured by the time it took to right themselves from an inverted wire screen. However, no deficiencies in Rotarod performance, grip strength, or open-field movements were detected at 6 months.

  3. X
    Neuronal Loss at 34

    Progressive loss of dopaminergic neurons was reported in the substantia nigra pars compacta (19 percent reduction at 8.5 months and 55 percent at 19 months).

Absent
  • α-synuclein Inclusions at

    Inclusions were not observed at any age. Diffuse α- synuclein protein was both cytoplasmic and nuclear.

No Data
  • Non-Motor Impairment at

    No data.

  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
SNCA SNCA A30P, SNCA A53T SNCA: Transgenic Parkinson's Disease

Progressively loss of dopaminergic neurons in the substantia nigra pars compacta, observed by 8.5 months. No α-synuclein inclusions. Morphological abnormalities in the dopaminergic system, including axonal and dendritic abnormalities, reduced dopamine concentration in the striatum.

More active as young adults, then hypoactive compared to non-Tg. Also reduced motor coordination in old age as measured by the time to right from an inverted wire screen.

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α-synuclein A53T Mouse (Tg)

Observed
  1. X
    Dopamine Deficiency at 23

    In symptomatic mice, striatal dopamine and metabolites DOPAC and HVA are comparable to wildtype, but at 5 months, striatal tyrosine hydroxylase is reduced.  Increased D1 receptors in the substantia nigra and decreased dopamine transporters in the nucleus accumbens and striatum have been reported.

  2. X
    Non-Motor Impairment at 50

    At 11–12 months, spatial memory was impaired as assessed by the Barnes circular maze.

  3. X
    α-synuclein Inclusions at 35

    Prior to motor deficits, these mice develop accumulations of α-synuclein in select neuronal populations, including the midbrain, cerebellum, brainstem, and spinal cord. The protein aggregates do not resemble Lewy bodies, but are thioflavin-S-positive, indicating fibrillar structure.

  4. X
    Neuroinflammation at 40

    In symptomatic mice, increased GFAP immunoreactivity was observed in select brain regions, including the dorsal midbrain, deep cerebellar nuclei, brainstem, and spinal cord. Cortex, hippocampus, and substantia nigra did not have increased reactivity compared with non-Tg controls.

  5. X
    Motor Impairment at 32

    These mice develop severe motor impairment starting around 9-16 months of age. The deficits start out with mild hyperactivity at 7 months and progress to a wobbling movement, decreased activity, and ultimately paralysis and death.

  6. X
    Mitochondrial Abnormalities at 56

    At 11–14 months, mitochondria in brainstem neurons were enlarged and their co-localization with the mitochondrial fission protein Drp1 was reduced.

Absent
  • Neuronal Loss at

    Overt neuronal loss was not reported in these mice.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
SNCA SNCA A53T SNCA: Transgenic Parkinson's Disease

No overt neuronal loss. Alterations in dopaminergic-associated proteins in the striatum, substantia nigra, and nucleus accumbens. Region-specific neuronal accumulation of fibrillar α-synuclein, ubiquitin, and neurofilament-H, and accompanying astrocytosis.

Early hyperactivity followed by severe motor impairment, manifesting as wobbling, posturing, decreased spontaneous locomotor behavior, inability to navigate the Rotarod, and ultimately paralysis and death. At 11–12 months, spatial memory impaired as assessed by the Barnes circular maze.

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α-synuclein A53T Mouse (Tg) on SNCA KO

Observed
  1. X
    Non-Motor Impairment at 14

    By 3 months of age, the mice develop gastrointestinal dysfunction.

  2. X
    Motor Impairment at 26

    By 6 months of age, homozygous mice became hypoactive, traveling less distance. This was not attributed to changes in exploratory behavior caused by anxiety. Also at 6 months, differences in performance on the accelerating Rotarod were seen.

Absent
  • Dopamine Deficiency at

    No differences in striatal dopamine concentrations, or dopaminergic metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) at 11 and 18 months of age.

  • α-synuclein Inclusions at

    No evidence of Lewy body-like inclusions in the brain at any age. Likewise α-synuclein aggregates were not observed in the brain, although they did occur in enteric neurons in the gut.

  • Neuronal Loss at

    No evidence of neuronal cell loss in the substantia nigra at 11 and 18 months of age, including dopaminergic neurons (TH-positive neurons) and total neurons.

No Data
  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
SNCA SNCA A53T SNCA: Transgenic; SNCA: Knock-Out Parkinson's Disease

No loss of dopaminergic neurons in the substantia nigra by 18 months of age. Rare dystrophic synapses in the hippocampus at advanced age, but no Lewy body-like pathology or α-synuclein aggregation in the brain. No change in striatal dopamine concentration.

Impaired performance on the Rotarod and reduced spontaneous locomotor activity in open-field test.

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α-synuclein E46K Rat (BAC Tg)

Observed
  1. X
    α-synuclein Inclusions at 52

    By 12 months of age, intracellular aggregates were observed in dopaminergic neurons of the substantia nigra and ventral tegmental area. Aggregates noted to be fairly small compared to those observed in PD brain. In the striatum and cortex α -synuclein accumulation appeared primarily in neuronal processes.

Absent
  • Dopamine Deficiency at

    No dopamine deficiency in the striatum at 12 months of age. No serotonin deficiency in the striatum. Dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid were reduced by approximately 25 percent and transmitter turnover was decreased.

  • Motor Impairment at

    No overt motor differences out to 12 months of age, unless challenged with low-dose rotenone, upon which the rats exhibit bradykinesia, postural instability, and rigidity.

  • Neuronal Loss at

    No overt loss of dopaminergic neurons out to 12 months of age.

No Data
  • Non-Motor Impairment at

    No data.

  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
SNCA SNCA E46K SNCA: Transgenic Parkinson's Disease

No overt neuronal loss. Accumulation of mutant α-synuclein in the brain, in the form of diffuse staining and intracellular aggregates. Aggregates were largely restricted to dopaminergic neurons of the substantia nigra and ventral tegmental area. Elevated nitrotyrosine in dopaminergic neurons.

No overt behavioral changes until challenged with low-dose rotenone, upon which the rats exhibit bradykinesia, postural instability, and rigidity.

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α-synuclein KO Mouse

Observed
  1. X
    Neuroinflammation at 16

    Microglia cultured from Snca KO brain were more reactive, ramified. They had vacuole-like structures. Snca KO microglia exhibited exacerbated response to LPS, with greater secretion of pro-inflammatory cytokines.

  2. X
    Motor Impairment at 26

    Motor function was largely intact. Normal performance on the Rotarod and in total distance travelled in the open field test. Subtle differences only (e.g., less rearing behavior than controls). They also spent less time in the center of the field, suggesting a possible anxiety-related phenotype.

  3. X
    Mitochondrial Abnormalities at 39

    Mitochondrial abnormalities include reduced levels of the mitochondrial phospholipid cardiolipin and reduced activity of electron transport chain complex I/III.

Absent
  • Non-Motor Impairment at

    The mice had normal reflexes and sensory abilities. Also, learning and memory appeared intact at 6-10 months of age, as assesed by the Morris water maze and tests of conditioned fear memory.

No Data
  • Dopamine Deficiency at

    A possible modest reduction in striatal dopamine level, but highly variable from mouse to mouse.

  • α-synuclein Inclusions at

    No data.

  • Neuronal Loss at

    No gross abnormalities in the brain.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
SNCA SNCA: Knock-Out Parkinson's Disease

No gross brain abnormalities. Electron microscopy revealed synaptic vesicle abnormalities in hippocampal neurons, i.e., fewer vesicles in the reserve pool.

Behavior is largely normal. Normal performance on the Rotarod. Subtle differences in locomotor activity (e.g., less rearing) but normal overall distance travelled. Learning and memory appear intact. Possible anxiety-like phenotype.

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α-synuclein KO Mouse (Conditional)

Observed
Absent
No Data
  • Dopamine Deficiency at

    No data.

  • Non-Motor Impairment at

    No data.

  • α-synuclein Inclusions at

    No data.

  • Neuroinflammation at

    No data.

  • Motor Impairment at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Neuronal Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
SNCA SNCA: Conditional Knock-out Parkinson's Disease

No data.

No data.

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ALS-related Research Models

Sex-specific differences

  • Cortical Neuron Loss
  • Lower Motor Neuron Loss
  • Cytoplasmic Inclusions
  • Gliosis
  • NMJ Abnormalities
  • Muscle Atrophy
  • Motor Impairment
  • Body Weight
  • Premature Death

AAV-GFP-(GA)50

  • Observed
  • No Data
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • No Data

At 6 months, neuron loss observed in cortex, including layer V of motor cortex.

No data.

Neuronal poly(GA)- and ubiquitin-positive inclusions already present at 4-6 weeks; rare TDP-43-positive inclusions.

Astrogliosis, but not microgliosis, in cortex and hippocampus, seen at 6 months.

No data.

No data.

Deficits in tail-suspension and rotarod tests, seen at 6 months.

Decreased body weight in males, but not females, seen at 6 months.

No data.

AAV-GFP–(GR)100

  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Absent
  • No Data

Fewer cortical neurons than controls, observed as early as 6 weeks of age.

Not observed up to 6 months of age.

Very rare TDP-43 inclusions, observed at 6 months.

Astrogliosis and microgliosis in cortex and hippocampus, observed at 6 weeks.

No data.

No data.

Progressive motor deficits, seen in open-field, rotarod, rod-walk, and wire-hang tests.

Normal at 6 months of age.

No data.

C9-BAC500 (Brown)

  • Absent
  • Absent
  • Observed
  • Absent
  • Absent
  • No Data
  • Absent
  • Absent
  • Absent

Not observed.

Not observed.

No cytoplasmic mislocalization, or aggregation of TDP-43 in the motor cortex. However, dipeptide repeats accumulated at advanced age and formed small perinuclear inclusion bodies positive for poly-GP.

No signs of increased activation of microglia or astrocytes in the brain or spinal cord.

No difference in denervation of neuromuscular junctions at 24 months of age. No difference in motor or sensory spinal nerve root axon number or morphology.

Muscle histology has not been reported, but no overt muscle atrophy was observed.

No overt motor deficit as measured by the Rotarod and grip strength.

Non-significant trend for male C9BAC mice to be heavier than non-Tg controls. Female data have not yet been reported.

Normal lifespan beyond 2 years in male mice. Female data have not yet been reported.

C9-BACexp (Baloh/Lutz)

  • Absent
  • Absent
  • Observed
  • Absent
  • Absent
  • Absent
  • Absent
  • Absent
  • Absent

Not observed.

Not observed.

RNA foci throughout the nervous system starting at 3 months of age. Foci comprised of RNA transcripts in both the sense and antisense directions. Age-associated formation of dipeptide aggregates, e.g., poly-GP.

No increase in GFAP staining in the brain and spinal cord compared with non-Tg controls, even at 18 months of age.

Not observed.

Not observed.

No abnormalities in grip strength, Rotarod performance, or open-field testing at a young age (3 months) or advanced age (18 months), compared with non-Tg controls.

No abnormalities in body weight at a young age (3 months) or advanced age (18 months) compared with non-Tg controls.

Normal lifespan.

C9orf72 Knock-out

  • Absent
  • Absent
  • Absent
  • Absent
  • Absent
  • Absent
  • Observed
  • Absent
  • Absent

Not observed.

Not observed.

Not observed.

Not observed.

Not observed.

Not observed.

Reduced activity on open-field test. No abnormalities in grip strength or Rotarod performance.

Not observed.

Not observed.

C9ORF72(AAV)(G4C2)149

  • Observed
  • No Data
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • No Data
  • No Data

Cortical neuron loss by 6 months.

No data.

Cytoplasmic inclusions containing dipeptide repeat proteins (DPRs) derived from sense RNA seen in the cortex, hippocampus, cerebellum, and spinal cord; inclusions containing DPRs produced from antisense transcripts seen in the cortex and occasionally in the hippocampus.

Astrogliosis in the cortex by 3 months.

No data.

No data.

Deficits in the hanging wire test emerge between 3 and 6 months.

No data.

No data.

C9ORF72(AAV)(G4C2)66

  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • No Data

Compared with mice expressing 2-repeats, the 66-repeat mice had 17 percent fewer neurons in the cortex at 6 months of age and 11 percent fewer Purkinje cells in the cerebellum. At this age neurons in the hippocampus and thalamus were not affected.

At 6 months, neuronal loss in the spinal cord was not detected.

By 6 months, inclusions of C9RAN dipeptides were present in neurons of the cortex and hippocampus, and to a lesser extent in the cerebellum and spinal cord. Inclusions contained polyGA, polyGP, and polyGR dipeptides and were largely ubiquitin-positive.

Astrogliosis in the cortex by 6 months.

No data.

No data.

At 6 months, 66-repeat mice perform as well as 2-repeat mice on the Rotarod on the first day of testing. However, they fail to improve during subsequent trials, suggesting impairments in coordination and/or motor learning.

At 6 months females had a lower body weight than mice expressing 2-repeats. Body weight did not differ in males.

No data.

CamKII;(GR)80

  • Observed
  • No Data
  • Absent
  • Observed
  • No Data
  • No Data
  • Absent
  • Absent
  • No Data

Neuron loss in the cortex, beginning between 3 and 6 months of age.

No data, but note that the transgene is not expressed in these neurons.

No TDP-43 inclusions seen in mice studied up to 8 months of age.

Microgliosis and astrogliosis evident at 6 and 9 months, respectively.

No data.

No data.

No difference between CamKII;(GR)80 mice and CamKII-tTA control mice up to 9 months of age.

No difference between CamKII;(GR)80 mice and CamKII-tTA control mice up to 11 months of age.

No data.

Endogenous Sod1 D83G

  • Observed
  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • Observed
  • Observed
  • Observed

Neuronal numbers comparable to wild-type at 15 weeks, but about 20 percent loss of upper motor neurons by 29 weeks. Neurons in layer V of the motor cortex appeared selectively vulnerable.

Neuronal numbers comparable to wild-type at 6 weeks, but loss occurred by 15 weeks. The neuronal loss then stabilized; it was not more severe at 52 weeks of age.

Not observed.

Gliosis, of both astrocytes and microglia, was evident in the spinal cord by 15 weeks. It was further elevated at 52 weeks.

Denervation of a hindlimb muscle, the extensor digitorum longus, was detected by 52 weeks of age, and a decreased number of motor units in the EDL muscle.

Muscle atrophy was not reported, although changes to the muscle composition and histochemistry were observed.

Both male and female mice develop a variety of progressive motor symptoms. Grip strength was reduced at 6 weeks of age. Tremors developed by about 5 months of age. Rotarod performance was impaired, at 23 weeks in females and 67 weeks in males.

Homozygous mice, both male and female, showed reduced body weight by 4 weeks of age in contrast to wild-type littermates. Loss of excessive body weight was the primary factor leading to euthanasia.

Males reach end-stage sooner than females (495 ± 22 versus 588 ± 24 days). Animals were sacrificed when weight loss exceeded 20 percent of maximum weight, in accordance with animal-use guidelines. This is likely explained by the development of hepatocellular carcinomas due to SOD1 loss of function.

FUS-R521C

  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

No detectable loss of cortical neurons; however, neurons in the sensorimotor cortex show reduced dendritic complexity and reduced synaptic density.

No detectable difference in spinal motor neurons at P0. At P16, about 20% loss of ChAT-positive neurons in the anterior horn of cervical spinal cord. At P30-P60, about 50% loss of anterior horn neurons. Remaining motor neurons show reduced dendritic complexity and synaptic density.

Less than 10% of spinal motor neurons have cytoplasmic FUS inclusions.

Prominent increase in microgliosis and astrogliosis in the anterior horn of the spinal cord by end stage.

Reduced innervation of neuromuscular junctions in the diaphragm.

The majority of mice have severe skeletal muscle atrophy in the hindlimb by end stage.

Early postnatal motor impairment, including abnormal hindlimb clasping when lifted by the tail, gait abnormalities, and impaired Rotarod performance.

Early postnatal growth is retarded, and the mice experience progressive loss of body weight.

The majority of mice in the N1F1 generation reached end stage and were sacrificed by postnatal day 100. Mice in subsequent generations live longer: about 40% reach end stage by postnatal day 200.

FUSDelta14 Knock-in

  • No Data
  • Observed
  • Absent
  • No Data
  • Observed
  • No Data
  • Observed
  • No Data
  • Observed

No data.

No lower motor neuron loss at 3 months but 14% reduction in the number of motor neurons in lumbar spinal cord at 12 months and 20% reduction by 18 months.

No increase in the number of spinal motor neurons that contain p62- or ubiquitin-positive inclusions in aged FUSDelta14 mice compared with aged wild-type mice.

No data.

Reduction in the number of intact neuromuscular junctions (fully innervated endplates) in hindlimb lumbrical muscles by 18 months of age.

No data.

Normal motor activity at 3 months of age but impaired hindlimb function by 15 months.

No data.

Reduced survival starting at 19 months of age.

FUSΔ14 (FUSd14)

  • Absent
  • Absent
  • Observed
  • Absent
  • No Data
  • No Data
  • Absent
  • No Data
  • No Data

Not observed.

Not observed.

Neuronal cytoplasmic inclusions were present by 3 months of age in the cerebral cortex. Inclusions occurred in about 20% of neurons and often co-labeled with ubiquitin.

No obvious astrogliosis or microglial activation at 3 months of age in the cerebral cortex.

No data.

No data.

When the mice were sacrificed at 3 months of age, they appeared healthy and displayed no obvious motor phenotype.

No data.

No data.

FusΔNLS

  • No Data
  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • Observed
  • Absent
  • Absent

No data.

Approximately 30% reduction of motor neuron numbers in the dorsal spinal cord.

Ubiquitin pathology was observed in motor neurons, but p62 inclusions were not.

Slight increase in oligodendrocytes in the spinal cord white matter.

Fibrillation and fasciculation potentials were observed in the gastrocnemius or tibialis anterior muscles. There was also a reduction in compound muscle action potential amplitude.

No data.

By 10 months, mice demonstrated irregular walking patterns and reduced hang time on the inverted grid test. No deficits in grip strength or rotarod performance. Paralysis was not observed.

By 22 months, no weight loss was observed.

Life span was not altered.

hFUS (+/+) (PrP-hFUS)

  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

In the brain, overt neuronal loss was absent at end stage (~11 weeks).

By end stage (~11 weeks), homozygous mice had lost about 60 percent of α-motor neurons in the anterior horn of the lumbar spinal cord.

By end stage, cytoplasmic FUS inclusions, described as “granular” and “globular,” develop in the spinal cord of homozygous mice. Ubiquitin-positive inclusions also develop, but do not co-localize with FUS inclusions. Neurons in the brain also develop “granular” and “skein-like” FUS inclusions.

By end stage (~11 weeks), homozygous mice had microgliosis and astrogliosis in the anterior horn of the spinal cord and in the white matter of the dorsal columns. Reactive gliosis was absent in the brain, despite cytoplasmic inclusions of FUS in some neurons.

Homozygous mice had about 20 percent fewer functional motor units in the extensor digitorum longus muscle as estimated by neurophysiological assessment.

Muscle histology from end stage (~11 weeks) homozygous mice showed focal muscle atrophy in hindlimb muscles.

Homozygous mice exhibited motor symptoms at four weeks of age, starting with a tremor and mild signs of hindlimb dysfunction, including gait abnormalities. Motor symptoms progressed quickly, ultimately developing into hindlimb paralysis.

Homozygous mice fail to gain weight normally starting about four weeks of age. Their body weight declines in subsequent weeks, often precipitating euthanasia.

Homozygous mice were euthanized between 10 and 13 weeks of age when they developed severe motor impairment or lost 25 percent of their body weight. Average survival was 82 ± 12 days.

hFUS-P525L

  • No Data
  • Observed
  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • Absent

No data.

Progressive loss of motor neurons at lumbar level 5.

No FUS inclusions were observed.

Astrocytosis and microgliosis were observed in the spinal cord.

Progressive denervation of hindlimb muscles. Decreased density of synaptic vesicles and mitochondria with normal morphologies. Altered electrophysiological properties.

Reduced fiber diameter in the tibialis anterior muscle.

Deficits in wire hang test at 360 days.

No data.

Not observed by 360 days.

hFUS-R521C

  • No Data
  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • No Data
  • Absent

No data.

Progressive loss of motor neurons at lumbar level 5.

No FUS inclusions were observed.

Astrocytosis and microgliosis were observed in the spinal cord.

Progressive denervation of hind limb muscles. 

No data.

No data.

No data.

Not observed by 360 days.

hPFN1-G118V

  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

At 202 days, there was a decrease in the number of corticospinal neurons of the motor cortex.

Progressive loss of ventral horn neurons from 165 through 202 days of age.

Spinal cord motor neurons had TDP-43 puncta.

Astrocytosis and microgliosis were observed in the spinal cord at end stage.

Denervation of gastrocnemius muscle at end stage. Muscle action potential also had reduced amplitude.

At 165 days, hind limb muscle atrophy was observed.

Progressive motor impairments began ~ 120 days. Mice demonstrated tremors, limb clasping, muscle weakness, gait abnormalities, as well as reduced locomotion and decreased performance on the Rotarod. 

Body weight peaked ~ 150 days and then progressively decreased.

Mice were sacrificed at an average of 202 days when they were unable to right themselves. Females on average reached 191 days while males attained 213 days.

hTDP-43ΔNLS

  • Observed
  • Absent
  • Absent
  • Observed
  • No Data
  • Absent
  • Observed
  • No Data
  • Absent

Severe neuronal degeneration in the dentate gyrus and deep layers of the neocortex. Other regions, such as the hippocampal CA1 subfield and olfactory bulb, were relatively resistant to neurodegeneration. Approximately 50 percent of dentate gyrus neurons were lost one month after the transgene was activated.

Not observed.

High levels of cytosolic TDP-43 but only very rare aggregates (observed in less than 1 percent of cortical neurons and even rarer in other brain regions, such as the hippocampus and striatum).

Severe astrogliosis and microgliosis in areas affected by neurodegeneration, including cortical and hippocampal regions, as well as the corticospinal tract.

Unknown.

Not observed.

Spastic motor impairment indicated by an abnormal clasping response as early as one week after transgene induction. A variety of motor deficits develop by one month after transgene induction, including impaired coordination on the Rotarod and decreased grip strength.

Unknown.

Not observed.

NEFH-tTA x hTDP-43ΔNLS

  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

Decreased cortical thickness indicative of neuronal degeneration beginning at four weeks off dox. By end stage, rNLS8 mice had significantly smaller brains than non-Tg littermates.

rNLS8 lost motor neurons in the lumbar spinal cord by six weeks off dox.

Cytoplasmic inclusions of TDP-43 occur as early as one week off dox in neurons in the brain. Inclusions accumulate over time and are present in many brain regions, including the motor cortex. TDP-43 inclusions are relatively rare in the spinal cord. Ubiquitin-positive inclusions are also seen.

Astrogliosis develops in many brain regions, including layer V of the motor cortex.

Denervation of the hindlimb muscle tibialis anterior was detectable by four weeks off dox, that is, two weeks prior to detectable loss of lower motor neurons.

At end-stage, rNLS8 mice exhibit gross muscle atrophy of the hindlimb muscles tibialis anterior and gastrocnemius.

rNLS8 mice develop a variety of motor impairments, starting with a deficit in hindlimb clasping and a fine tremor in the forelimb and/or hindlimb. They also develop progressive loss of grip strength (as measured by the wire-hang test) and a progressive decline in coordinated movement and balance (as measured by the accelerating Rotarod).

Body mass peaked at approximately 7 weeks of age (i.e., two weeks off dox) and then progressively dropped. Excessive loss of body weight (>30% decrease from peak weight) often defined end-stage.

rNLS8 mice die prematurely. They reach end-stage 8-18 weeks off dox, with a median survival of 10.3 weeks off dox.

PFN1-C71G

  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

No neuronal loss in the cortex but neurodegeneration in medulla.

By 4 months there was a loss of cervical motor neurons and an increase in degenerating axons.

Cytoplasmic inclusions of PFN1, ubiquitin, and p62 in motor neurons around 6 months.

Microgliosis and astrogliosis observed in the dorsal horn by 5 months.

Denervation of gastrocnemius muscle occurs by 5 months.

Muscle atrophy in lower hind limb occurs by 6 months.

By 4 months, mice began showing minor gate changes and at 5-6 months they began demonstrating progressive deficits in Rotorod performance, vertical behaviors, and grip strength. 

Body weight peaked at 4-6 months and then progressively decreased.

Mice were sacrificed when they were incapable of locomotion following the paralysis of two or more limbs which occurred around 7 months of age.

PrP-hFUS (R495X)

  • Absent
  • Absent
  • Absent
  • No Data
  • Observed
  • No Data
  • Absent
  • No Data
  • Observed

Not observed.

Not observed.

Despite high levels of cytoplasmic FUS, neuronal inclusions were not observed.

No data.

A number of abnormalities were detected in the hindlimb musculature by electromyography (EMG). These phenotypes were detectable by 8-12 months of age and included fibrillation potentials, muscle denervation, and a reduction in the number of motor units.

No data.

Not observed.

No data.

Hemizygous mice sporadically developed intestinal swelling leading to premature death (mean survival 118 days). Homozygous mice were more severely affected (50 percent of the original cohort died around 59 days of age).

PrP-hFUS (WT)

  • No Data
  • No Data
  • Absent
  • No Data
  • Absent
  • No Data
  • Absent
  • No Data
  • Observed

No data.

No data.

Not observed.

No data.

Not observed.

No data.

Not observed.

No data.

Hemizygous mice die prematurely following a brief illness characterized by poor feeding. Mean survival of hemizygotes ~203 days.

SOD1 (G37R)

  • Absent
  • Observed
  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

Upper motor neuron loss was not observed, although vacuolization occurred in brainstem neurons.

Motor neurons in the spinal cord and brainstem degenerated with overt neuronal loss in the ventral horn in some regions of the spinal cord by 19 weeks. The degenerative process involved extensive vacuolization.

Not observed.

Astrogliosis occurs in the spinal cord by 11 weeks of age, becoming more severe with age.

Denervated endplates have been observed.

Loss of motor axons, denervated endplates, atrophy of muscle fibers, and fiber type grouping observed by end-stage.

Motor impairment at 4-6 months, beginning with reduced spontaneous movement, then tremors, limb weakness, and poor grooming. Eventual paralysis of the hindlimbs.

Loss of body weight is observed.

Mice survive about 6 to 8 months.

SOD1-G85R (hybrid)

  • No Data
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

Unknown.

Extensive degeneration of large spinal axons coincident with the onset of clinical symptoms. By end stage, motor neurons in the ventral horn are lost.

Astrocytic inclusions occur early, about 6 months of age. The inclusions are immunoreactive for SOD1 and ubiquitin.

Astrogliosis and microgliosis are observed in the spinal cord starting around 6.5 months of age, and become more severe with age.

Denervation of muscle fibers is observed.

Hemizygous mice develop muscle weakness around 9 months of age, coincident with atrophy and denervation of muscle fibers.

Progressive motor impairment generally starting around 8 months with reduced grip strength in one hindlimb, rapidly spreading to other limbs and leading to paralysis within about two weeks.

Hemizygous mice start to lose weight at about 9 months of age.

End stage is characterized by paralysis at about 10 months of age.

SOD1-G93A (hybrid) (G1H)

  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

Although outright upper motor neuron loss is absent or rare, degenerative signs (e.g., swollen neurites, Gallyas-positive aggregates, vacuoles, and neuritic spheroids) have been shown in motor regions of the cerebral cortex by five months of age.

Up to 50% loss of motor neurons in the cervical and lumbar segments of the spinal cord at end stage.

Inclusions accumulate in spinal motor neurons starting around 82 days of age. Inclusions generally take the form of spheroids or Lewy-body-like inclusions and commonly include a variety of neuronal intermediate filament proteins. TDP-43-positive inclusions are not present.

Gliosis, including the proliferation of reactive microglia and astrocytes, develops in parallel with motor neuron degeneration in the spinal cord.

Neuromuscular junctions degenerate around 47 days of age; fast-fatiguable motor neurons are affected first.

Longitudinal MRI has shown reduced muscle volume as early as 8 weeks of age. Atrophy is progressive. Skeletal muscle is affected, including limb and diaphragm.

Signs of motor impairment begin at about 3 months of age with a shaking tremor that leads to paralysis.

One of the first signs of illness is a slowing of growth and a plateauing of weight.

G1H mice reach end-stage disease by 5 months of age. Females typically survive longer than males.

TARDBP (A315T) (congenic)

  • No Data
  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

These mice lose corticospinal tract axons, but outright loss of cortical neurons has not been reported in the model. When crossed with a Thy-1YFP model to label layer 5 pyramidal neurons, mice expressing TDP-43 (A315T) had fewer neurons at 15 weeks of age than YFP littermate controls (Zhang et al., 2016).

Most studies reported no lower motor neuron loss. One study observed 20% loss of large ventral horn neurons, possibly dependent on diet and how long the mice live in an individual colony.

Ubiquitinated inclusions in the cytoplasm of spinal motor neurons and cortical layer V neurons. No evidence for cytoplasmic TDP-43 inclusions.

Reports of astrocytosis in cortical layer 5 and in the spinal cord, as well as microgliosis in the spinal cord.

Denervation of neuromuscular junctions at end stage (~11% on normal diet; ~20% loss on a gel diet).

Atrophy of gastrocnemius muscle (gel diet).

Deficits have been reported in nonspecific measures of strength and coordination such as the Rotarod (males and females) and hanging-wire test (males). A severely impaired gait (“swimming gait”) was observed in mice fed a gel diet.

Weight loss is a consistent feature. Potentially confounded by severe gut phenotype.

Survival is limited by severe gastrointestinal dysfunction and can be prolonged with a gel diet. Lifespan varies, but in general on a standard diet males live about 3 months and females about 6 months.

TARDBP (A315T) (hybrid)

  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • Observed
  • Observed
  • Observed
  • Observed

By end-stage, neuronal numbers in layer 5 of the motor cortex are decreased with about 50 percent loss of corticospinal tract axons.

By end-stage, ~20% loss of motor neurons in the L3-L5 region of the spinal cord.

By end-stage, cytoplasmic inclusions of ubiquitinated proteins in layer 5 neurons of motor, sensory, and cingulate cortex. Ubiquitin aggregates in ventral horn neurons. TDP-43 inclusions were rare.

By end-stage, selective increase in GFAP immunoreactivity in cortical layer 5.

Unknown.

By end-stage, atrophic muscle fibers were observed.

Gait abnormalities around three months of age, developing into a characteristic “swimming gait” by four to five months.

Weight was comparable to non-Tg mice at birth. By 4.5 months transgenic mice began to lose weight.

Survival for about 5 months (154 ± 19 days) before dying spontaneously or being euthanized. It was not reported if this analysis includes males, females, or both.

Tardbp Q331K Knock-In

  • No Data
  • No Data
  • No Data
  • No Data
  • No Data
  • No Data
  • No Data
  • No Data
  • No Data

No data.

No data.

No data.

No data.

No data.

No data.

No data.

No data.

No data.

Tardp LCDmut

  • No Data
  • Observed
  • Observed
  • No Data
  • Observed
  • No Data
  • Observed
  • No Data
  • Absent

No data.

28 percent reduction in the number of motor neurons in the sciatic motor neuron pool, compared with non-transgenic littermates.

At 18 months of age, p62- and ubiquitin-positive inclusions are found in the ventral regions of the spinal cord, although these inclusions do not appear to be located in the cytoplasm of motor neurons.

No data.

By 24 months, a 15 percent reduction in motor units innervating the extensor digitorum muscle.

No data.

Grip strength in both male and female mice begins to decline at 12 months of age. By 24 months, there is a nearly 40 percent reduction in force measured in tibialis anterior muscles.

No data.

Do not exhibit premature death, at least until 24 months of age.

Tardp_RRM2mut

  • No Data
  • Absent
  • Absent
  • No Data
  • Absent
  • No Data
  • Absent
  • No Data
  • Absent

No data.

Not observed at 2 years.

Not observed at 2 years.

No data.

Not observed at 2 years.

No data.

Not observed at 2 years.

No data.

Homozygous mutation is embryonic lethal.

TDP-43 (A315T)

  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • No Data
  • Absent

Not observed.

Not observed.

Cytoplasmic accumulation of TDP-43 was observed by 10 months of age in the spinal cord. Furthermore, cytoplasmic aggregates were observed and often co-localized with ubiquitin. These inclusions are not detected at three months of age.

Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.

Unknown.

Unknown.

At 38 weeks of age, mice develop impairments on the accelerating Rotarod relative to non-Tg littermates.

Unknown.

Not observed.

TDP-43 (A315T) (line 23)

  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • Observed
  • Observed
  • Observed
  • Observed

Not observed.

Not observed.

Ubiquitin-positive cytoplasmic inclusions in neurons of the ventral horn and brainstem. Cytoplasmic aggregates of TDP-43 are largely absent, although rare phospho-TDP-43 inclusions were observed, especially at end-stage.

Mice exhibiting muscle weakness had astrocytosis in the ventral horn of the spinal cord.

Unknown.

Atrophy of muscle fibers in the quadriceps muscle of weak mice observed by day 44.

Progressive motor impairment, characterized by weakness, a decline in grip strength, and reduction in stride length. Weakness was usually more pronounced in the hindlimbs.

Progressive weight loss.

Line 23 mice survived about 2.5 months, mean survival 75 days. It was not reported whether this survival analysis includes males, females or both. Colony at Jackson Labs has longer mean survival.

TDP-43 (G348C)

  • Absent
  • Absent
  • Observed
  • Observed
  • Observed
  • No Data
  • Observed
  • No Data
  • Absent

Not observed.

Not observed.

Cytoplasmic accumulation of TDP-43 was observed by 10 months in the spinal cord. Cytoplasmic aggregates occurred and often co-localized with ubiquitin. These inclusions are not detected at 3 months of age.

Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.

In 10-month-old mice, approximately 10% of NMJs in the gastrocnemius muscle were denervated, with another 20% partially denervated.

Unknown.

Performance on the Rotarod was comparable to non-Tg littermates until 36 weeks of age, and became progressively worse with age.

Unknown.

Normal lifespan.

TDP-43 (M337V)

  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

Not observed.

Not observed.

TDP-43 protein was largely nuclear, although some cytoplasmic TDP-43 was also observed. Some mild cytoplasmic inclusions were reported.

Reactive astrocytes and activated microglia proliferate in the spinal cord and brainstem.

No data.

No data.

Body tremors apparent by day 21 and the mice had difficulty recruiting their hindlimbs, leading to an irregular gait pattern, described as “dragging.”

 

By one month of age, homozygotes have reduced body weight compared to non-Tg littermates.

 

70% mortality of homozygotes by around one month of age.

TDP-43 (M337V) (Mt-TAR6/6)

  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

Severe neuronal loss in all CA regions of the hippocampus of homozygous mice. Neuronal loss was also observed in layer V cortical neurons and thalamic neurons.

Neuronal loss was observed in the spinal cords of homozygous mice.

Some homozygous mice developed cytoplasmic inclusions in layer V cortical neurons. These were often, but not always, ubiquitin–positive. They were not universally observed, even in end-stage mice.

Elevated astrogliosis and microgliosis compared with non-Tg controls, especially in the motor cortex and spinal cord. Gliosis in the hippocampus was seen at end stage.

Unknown.

Unknown.

Motor impairment developed quickly, by 11 days of age in homozygous mice, starting with an abnormal clasping reflex. They also develop a hunched posture, muscle twitches, and reduced mobility. Paralysis developed within days, leading to death. Hemizygotes do not develop motor symptoms until about one year of age, and impairment varied from mouse to mouse.

Early postnatal growth retardation in homozygous mice. By day 17 their average body weight is about half that of non-Tg controls.

Homozygous mice survived an average of just 17 days. In contrast, hemizygous Mt-TAR6 mice lived up to 24 months (average survival ~16.4 months).

TDP-43 (Q331K)

  • No Data
  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • Observed
  • No Data
  • No Data

Unknown.

Age-dependent loss of lower motor neurons in the lumbar spinal cord. Loss is detectable as early as 2 months of age and is more pronounced by 10 months.

TDP-43 in the brain and spinal cord was predominantly nuclear. Cytoplasmic TDP-43 aggregates were absent.

Elevated astrogliosis and microgliosis in the ventral horn of spinal cord by 10-12 months of age compared with non-Tg controls.

Reduction in neuromuscular junction endplates by 10-12 months of age. Remaining NMJs often had a “bleb-like” appearance.

Muscle fiber abnormalities including centralized nuclei and damage by 10-12 months of age.

Tremor, abnormal hindlimb clasping, impaired performance on the Rotarod were detectable starting around 3 months of age. Reduced grip strength occurred later.

Unknown.

Unknown.

TDP-43 (Q331K) Knock-In (Line 52)

  • Observed
  • Absent
  • Absent
  • No Data
  • Absent
  • No Data
  • Absent
  • Observed
  • Observed

25% loss of parvalbumin-positive neurons at 5 months.

Not observed.

Not observed.

Unknown.

Not observed.

Unknown.

Not observed.

Increased body weight.

Mutation may be deleterious to male embryos.

TDP-43 (WT) (Elliott)

  • Absent
  • Absent
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed
  • Observed

Not observed.

Not observed.

Cytoplasmic ubiquitin-positive inclusions in skeletal muscle cells. Some TDP-43 inclusions, too.

No data.

No data.

An analysis of the quadriceps muscle, showed signs of myopathy, including variable muscle fiber size and disorganization of the muscle architecture.

Progressive motor impairment starting with external rotation of one hind limb followed by bilateral weakness and low muscle tone. Variable penetrance of this phenotype.

Progressive weight loss.

The mean survival of hemizygous mice was 109 days (it is not clear if this value represents males, females, or both).

TDP-43 (WT) (Julien model)

  • Absent
  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • Observed
  • No Data
  • No Data

Not observed.

Not observed.

Primarily nuclear localization of human TDP-43.

Gliosis, both microgliosis and astrogliosis, occur early in the brain and spinal cord. Reactive glia were detected as early as 3 months of age, with more by 10 months.

Some NMJ denervation was observed by 10 months of age. About 5% of NMJs at the gastrocnemius muscle were denervated, with another 20 percent partially denervated.

No data.

Decreased performance on the accelerating Rotarod at 42 weeks of age. Further impairment at 52 weeks.

No data.

No data.

TDP-43 (WT) (Kumar-Singh)

  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

In homozygous mice, quantitative loss of neurons occurs in the motor cortex compared with non-Tg littermates. Both superficial and deep cortical layers of the anterior cortex are affected.

By day 18, homozygous mice exhibited about 25 percent loss of motor neurons in the lumbar spinal cord compared with non-Tg littermates.

Homozygous mice developed cytoplasmic inclusions in the brain and spinal cord, many of which were ubiquitin-positive. A minority of inclusions co-labeled with TDP-43. Ultrastructural analysis revealed ubiquitin–negative cytoplasmic inclusions in anterior horn neurons to be abnormal accumulations of mitochondria.

Astrogliosis and microgliois especially in cortical layer V of the anterior cortex, including motor and somatosensory cortex, and in the spinal cord.

No data.

No data.

Homozygous mice exhibit an abnormal clasping reflex by postnatal day 14. Other early motor deficits include a shortened stride, a wide stance, and frequent stumbling. By day 18, reduced performance on the Rotarod. Complete paralysis occurs ~10 days after onset.

Size and weight of homozygous mice lag behind hemizygotes and non-Tg littermates.

Homozygous mice survive an average of just 24 days. In contrast, hemizygous mice survive to advanced age, although they die more prematurely than non-Tg mice, after 22 to 24 months.

TDP-43 (WT) (Petrucelli)

  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • Absent
  • Observed
  • Observed
  • Observed

Not observed.

Neuronal loss was not detected in spinal cords of homozygous mice as assessed by TUNEL staining and caspase-3 staining.

Cytoplasmic eosinophilic aggregates in spinal motor neurons by one month of age in homozygous mice.

Astrogliosis and microgliosis in the anterior horn of the spinal cord by one month of age.

Unknown.

Atrophy of the gastrocnemius muscle was not observed.

By day 21, homozygous mice displayed body tremors and mild gait impairment which progressed into a “swimming gait” and severe motor impairment.

Homozygotes diverge early from non-Tg littermates in terms of body weight, showing significantly reduced weight gain.

 

Homozygous mice were sacrificed at one to two months of age when they were unable to right themselves.

TDP-43 (Wt-TAR6/6)

  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • Observed
  • Observed
  • Observed
  • Observed

Approximate 15 percent loss of layer V neurons in motor cortex at 6 months.

Spinal motor neuron loss observed at 3 months, with approximately 10 percent fewer anterior horn neurons in lumbosacral regions at 6 months, compared with non-transgenic mice.

Inclusions containing phosphorylated TDP-43 rarely observed in the nuclei and cytoplasm of spinal neurons.

Microgliosis in cortex and spinal cord prominent at 6 months; astrogliosis in cortex and spinal cord apparent at 1.5 months.

No data.

Muscle wasting, particularly in flanks.

Progressive motor impairment; abnormal hind limb reflexes observed as early as 1.5 months.

TAR6/6 mice had lower body weights than non-transgenic mice between 3.25 and 3.75 months age, but the two genotypes were similar at younger and older ages (at least until 4.25 months).

Average survival is 6.7 months.

ΔNLS-FUS

  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

By 1 year, there was neuronal loss in the motor cortex.

Not observed at 1 year in the L5 anterior horn.

Ubiquitin- and p62-positive ΔNLS-FUS inclusions in motor cortex neurons.  

Microgliosis and astrocytosis were observed in the motor cortex.

No data.

No data.

Progressive motor impairments by 12 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as decreased performance on the Rotarod and hanging wire tests.

Decreased by 48 weeks.

Approximately 50% mortality by 60 weeks of age.

ΔNLS-FUS x TDP-43(WT)

  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

By 1 year, there was neuronal loss in the motor cortex.

Not observed at 1 year in the L5 anterior horn.

Ubiquitin- and p62-positive ΔNLS-FUS inclusions in motor cortex neurons.  

Microgliosis and astrocytosis were observed in the motor cortex.

No data.

No data.

Progressive motor impairments by 8 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as decreased performance on the Rotarod and hanging wire test.

Decreased by 48 weeks.

Approximately 40% mortality by 60 weeks of age.

ALS-related Research Models

  • Sex-specific differences
  • Cortical Neuron Loss
  • Lower Motor Neuron Loss
  • Cytoplasmic Inclusions
  • Gliosis
  • NMJ Abnormalities
  • Muscle Atrophy
  • Motor Impairment
  • Body Weight
  • Premature Death

AAV-GFP-(GA)50

Observed

At 6 months, neuron loss observed in cortex, including layer V of motor cortex.

No Data

No data.

Observed

Neuronal poly(GA)- and ubiquitin-positive inclusions already present at 4-6 weeks; rare TDP-43-positive inclusions.

Observed

Astrogliosis, but not microgliosis, in cortex and hippocampus, seen at 6 months.

No Data

No data.

No Data

No data.

Observed

Deficits in tail-suspension and rotarod tests, seen at 6 months.

Observed

Decreased body weight in males, but not females, seen at 6 months.

No Data

No data.

AAV-GFP–(GR)100

Observed

Fewer cortical neurons than controls, observed as early as 6 weeks of age.

Absent

Not observed up to 6 months of age.

Observed

Very rare TDP-43 inclusions, observed at 6 months.

Observed

Astrogliosis and microgliosis in cortex and hippocampus, observed at 6 weeks.

No Data

No data.

No Data

No data.

Observed

Progressive motor deficits, seen in open-field, rotarod, rod-walk, and wire-hang tests.

Absent

Normal at 6 months of age.

No Data

No data.

C9-BAC500 (Brown)

Absent

Not observed.

Absent

Not observed.

Observed

No cytoplasmic mislocalization, or aggregation of TDP-43 in the motor cortex. However, dipeptide repeats accumulated at advanced age and formed small perinuclear inclusion bodies positive for poly-GP.

Absent

No signs of increased activation of microglia or astrocytes in the brain or spinal cord.

Absent

No difference in denervation of neuromuscular junctions at 24 months of age. No difference in motor or sensory spinal nerve root axon number or morphology.

No Data

Muscle histology has not been reported, but no overt muscle atrophy was observed.

Absent

No overt motor deficit as measured by the Rotarod and grip strength.

Absent

Non-significant trend for male C9BAC mice to be heavier than non-Tg controls. Female data have not yet been reported.

Absent

Normal lifespan beyond 2 years in male mice. Female data have not yet been reported.

C9-BACexp (Baloh/Lutz)

Absent

Not observed.

Absent

Not observed.

Observed

RNA foci throughout the nervous system starting at 3 months of age. Foci comprised of RNA transcripts in both the sense and antisense directions. Age-associated formation of dipeptide aggregates, e.g., poly-GP.

Absent

No increase in GFAP staining in the brain and spinal cord compared with non-Tg controls, even at 18 months of age.

Absent

Not observed.

Absent

Not observed.

Absent

No abnormalities in grip strength, Rotarod performance, or open-field testing at a young age (3 months) or advanced age (18 months), compared with non-Tg controls.

Absent

No abnormalities in body weight at a young age (3 months) or advanced age (18 months) compared with non-Tg controls.

Absent

Normal lifespan.

C9orf72 Knock-out

Absent

Not observed.

Absent

Not observed.

Absent

Not observed.

Absent

Not observed.

Absent

Not observed.

Absent

Not observed.

Observed

Reduced activity on open-field test. No abnormalities in grip strength or Rotarod performance.

Absent

Not observed.

Absent

Not observed.

C9ORF72(AAV)(G4C2)149

Observed

Cortical neuron loss by 6 months.

No Data

No data.

Observed

Cytoplasmic inclusions containing dipeptide repeat proteins (DPRs) derived from sense RNA seen in the cortex, hippocampus, cerebellum, and spinal cord; inclusions containing DPRs produced from antisense transcripts seen in the cortex and occasionally in the hippocampus.

Observed

Astrogliosis in the cortex by 3 months.

No Data

No data.

No Data

No data.

Observed

Deficits in the hanging wire test emerge between 3 and 6 months.

No Data

No data.

No Data

No data.

C9ORF72(AAV)(G4C2)66

Observed

Compared with mice expressing 2-repeats, the 66-repeat mice had 17 percent fewer neurons in the cortex at 6 months of age and 11 percent fewer Purkinje cells in the cerebellum. At this age neurons in the hippocampus and thalamus were not affected.

Absent

At 6 months, neuronal loss in the spinal cord was not detected.

Observed

By 6 months, inclusions of C9RAN dipeptides were present in neurons of the cortex and hippocampus, and to a lesser extent in the cerebellum and spinal cord. Inclusions contained polyGA, polyGP, and polyGR dipeptides and were largely ubiquitin-positive.

Observed

Astrogliosis in the cortex by 6 months.

No Data

No data.

No Data

No data.

Observed

At 6 months, 66-repeat mice perform as well as 2-repeat mice on the Rotarod on the first day of testing. However, they fail to improve during subsequent trials, suggesting impairments in coordination and/or motor learning.

Observed

At 6 months females had a lower body weight than mice expressing 2-repeats. Body weight did not differ in males.

No Data

No data.

CamKII;(GR)80

Observed

Neuron loss in the cortex, beginning between 3 and 6 months of age.

No Data

No data, but note that the transgene is not expressed in these neurons.

Absent

No TDP-43 inclusions seen in mice studied up to 8 months of age.

Observed

Microgliosis and astrogliosis evident at 6 and 9 months, respectively.

No Data

No data.

No Data

No data.

Absent

No difference between CamKII;(GR)80 mice and CamKII-tTA control mice up to 9 months of age.

Absent

No difference between CamKII;(GR)80 mice and CamKII-tTA control mice up to 11 months of age.

No Data

No data.

Endogenous Sod1 D83G

Observed

Neuronal numbers comparable to wild-type at 15 weeks, but about 20 percent loss of upper motor neurons by 29 weeks. Neurons in layer V of the motor cortex appeared selectively vulnerable.

Observed

Neuronal numbers comparable to wild-type at 6 weeks, but loss occurred by 15 weeks. The neuronal loss then stabilized; it was not more severe at 52 weeks of age.

Absent

Not observed.

Observed

Gliosis, of both astrocytes and microglia, was evident in the spinal cord by 15 weeks. It was further elevated at 52 weeks.

Observed

Denervation of a hindlimb muscle, the extensor digitorum longus, was detected by 52 weeks of age, and a decreased number of motor units in the EDL muscle.

No Data

Muscle atrophy was not reported, although changes to the muscle composition and histochemistry were observed.

Observed

Both male and female mice develop a variety of progressive motor symptoms. Grip strength was reduced at 6 weeks of age. Tremors developed by about 5 months of age. Rotarod performance was impaired, at 23 weeks in females and 67 weeks in males.

Observed

Homozygous mice, both male and female, showed reduced body weight by 4 weeks of age in contrast to wild-type littermates. Loss of excessive body weight was the primary factor leading to euthanasia.

Observed

Males reach end-stage sooner than females (495 ± 22 versus 588 ± 24 days). Animals were sacrificed when weight loss exceeded 20 percent of maximum weight, in accordance with animal-use guidelines. This is likely explained by the development of hepatocellular carcinomas due to SOD1 loss of function.

FUS-R521C

Absent

No detectable loss of cortical neurons; however, neurons in the sensorimotor cortex show reduced dendritic complexity and reduced synaptic density.

Observed

No detectable difference in spinal motor neurons at P0. At P16, about 20% loss of ChAT-positive neurons in the anterior horn of cervical spinal cord. At P30-P60, about 50% loss of anterior horn neurons. Remaining motor neurons show reduced dendritic complexity and synaptic density.

Observed

Less than 10% of spinal motor neurons have cytoplasmic FUS inclusions.

Observed

Prominent increase in microgliosis and astrogliosis in the anterior horn of the spinal cord by end stage.

Observed

Reduced innervation of neuromuscular junctions in the diaphragm.

Observed

The majority of mice have severe skeletal muscle atrophy in the hindlimb by end stage.

Observed

Early postnatal motor impairment, including abnormal hindlimb clasping when lifted by the tail, gait abnormalities, and impaired Rotarod performance.

Observed

Early postnatal growth is retarded, and the mice experience progressive loss of body weight.

Observed

The majority of mice in the N1F1 generation reached end stage and were sacrificed by postnatal day 100. Mice in subsequent generations live longer: about 40% reach end stage by postnatal day 200.

FUSDelta14 Knock-in

No Data

No data.

Observed

No lower motor neuron loss at 3 months but 14% reduction in the number of motor neurons in lumbar spinal cord at 12 months and 20% reduction by 18 months.

Absent

No increase in the number of spinal motor neurons that contain p62- or ubiquitin-positive inclusions in aged FUSDelta14 mice compared with aged wild-type mice.

No Data

No data.

Observed

Reduction in the number of intact neuromuscular junctions (fully innervated endplates) in hindlimb lumbrical muscles by 18 months of age.

No Data

No data.

Observed

Normal motor activity at 3 months of age but impaired hindlimb function by 15 months.

No Data

No data.

Observed

Reduced survival starting at 19 months of age.

FUSΔ14 (FUSd14)

Absent

Not observed.

Absent

Not observed.

Observed

Neuronal cytoplasmic inclusions were present by 3 months of age in the cerebral cortex. Inclusions occurred in about 20% of neurons and often co-labeled with ubiquitin.

Absent

No obvious astrogliosis or microglial activation at 3 months of age in the cerebral cortex.

No Data

No data.

No Data

No data.

Absent

When the mice were sacrificed at 3 months of age, they appeared healthy and displayed no obvious motor phenotype.

No Data

No data.

No Data

No data.

FusΔNLS

No Data

No data.

Observed

Approximately 30% reduction of motor neuron numbers in the dorsal spinal cord.

Observed

Ubiquitin pathology was observed in motor neurons, but p62 inclusions were not.

Observed

Slight increase in oligodendrocytes in the spinal cord white matter.

Observed

Fibrillation and fasciculation potentials were observed in the gastrocnemius or tibialis anterior muscles. There was also a reduction in compound muscle action potential amplitude.

No Data

No data.

Observed

By 10 months, mice demonstrated irregular walking patterns and reduced hang time on the inverted grid test. No deficits in grip strength or rotarod performance. Paralysis was not observed.

Absent

By 22 months, no weight loss was observed.

Absent

Life span was not altered.

hFUS (+/+) (PrP-hFUS)

Absent

In the brain, overt neuronal loss was absent at end stage (~11 weeks).

Observed

By end stage (~11 weeks), homozygous mice had lost about 60 percent of α-motor neurons in the anterior horn of the lumbar spinal cord.

Observed

By end stage, cytoplasmic FUS inclusions, described as “granular” and “globular,” develop in the spinal cord of homozygous mice. Ubiquitin-positive inclusions also develop, but do not co-localize with FUS inclusions. Neurons in the brain also develop “granular” and “skein-like” FUS inclusions.

Observed

By end stage (~11 weeks), homozygous mice had microgliosis and astrogliosis in the anterior horn of the spinal cord and in the white matter of the dorsal columns. Reactive gliosis was absent in the brain, despite cytoplasmic inclusions of FUS in some neurons.

Observed

Homozygous mice had about 20 percent fewer functional motor units in the extensor digitorum longus muscle as estimated by neurophysiological assessment.

Observed

Muscle histology from end stage (~11 weeks) homozygous mice showed focal muscle atrophy in hindlimb muscles.

Observed

Homozygous mice exhibited motor symptoms at four weeks of age, starting with a tremor and mild signs of hindlimb dysfunction, including gait abnormalities. Motor symptoms progressed quickly, ultimately developing into hindlimb paralysis.

Observed

Homozygous mice fail to gain weight normally starting about four weeks of age. Their body weight declines in subsequent weeks, often precipitating euthanasia.

Observed

Homozygous mice were euthanized between 10 and 13 weeks of age when they developed severe motor impairment or lost 25 percent of their body weight. Average survival was 82 ± 12 days.

hFUS-P525L

No Data

No data.

Observed

Progressive loss of motor neurons at lumbar level 5.

Absent

No FUS inclusions were observed.

Observed

Astrocytosis and microgliosis were observed in the spinal cord.

Observed

Progressive denervation of hindlimb muscles. Decreased density of synaptic vesicles and mitochondria with normal morphologies. Altered electrophysiological properties.

Observed

Reduced fiber diameter in the tibialis anterior muscle.

Observed

Deficits in wire hang test at 360 days.

No Data

No data.

Absent

Not observed by 360 days.

hFUS-R521C

No Data

No data.

Observed

Progressive loss of motor neurons at lumbar level 5.

Absent

No FUS inclusions were observed.

Observed

Astrocytosis and microgliosis were observed in the spinal cord.

Observed

Progressive denervation of hind limb muscles. 

No Data

No data.

No Data

No data.

No Data

No data.

Absent

Not observed by 360 days.

hPFN1-G118V

Observed

At 202 days, there was a decrease in the number of corticospinal neurons of the motor cortex.

Observed

Progressive loss of ventral horn neurons from 165 through 202 days of age.

Observed

Spinal cord motor neurons had TDP-43 puncta.

Observed

Astrocytosis and microgliosis were observed in the spinal cord at end stage.

Observed

Denervation of gastrocnemius muscle at end stage. Muscle action potential also had reduced amplitude.

Observed

At 165 days, hind limb muscle atrophy was observed.

Observed

Progressive motor impairments began ~ 120 days. Mice demonstrated tremors, limb clasping, muscle weakness, gait abnormalities, as well as reduced locomotion and decreased performance on the Rotarod. 

Observed

Body weight peaked ~ 150 days and then progressively decreased.

Observed

Mice were sacrificed at an average of 202 days when they were unable to right themselves. Females on average reached 191 days while males attained 213 days.

hTDP-43ΔNLS

Observed

Severe neuronal degeneration in the dentate gyrus and deep layers of the neocortex. Other regions, such as the hippocampal CA1 subfield and olfactory bulb, were relatively resistant to neurodegeneration. Approximately 50 percent of dentate gyrus neurons were lost one month after the transgene was activated.

Absent

Not observed.

Absent

High levels of cytosolic TDP-43 but only very rare aggregates (observed in less than 1 percent of cortical neurons and even rarer in other brain regions, such as the hippocampus and striatum).

Observed

Severe astrogliosis and microgliosis in areas affected by neurodegeneration, including cortical and hippocampal regions, as well as the corticospinal tract.

No Data

Unknown.

Absent

Not observed.

Observed

Spastic motor impairment indicated by an abnormal clasping response as early as one week after transgene induction. A variety of motor deficits develop by one month after transgene induction, including impaired coordination on the Rotarod and decreased grip strength.

No Data

Unknown.

Absent

Not observed.

NEFH-tTA x hTDP-43ΔNLS

Observed

Decreased cortical thickness indicative of neuronal degeneration beginning at four weeks off dox. By end stage, rNLS8 mice had significantly smaller brains than non-Tg littermates.

Observed

rNLS8 lost motor neurons in the lumbar spinal cord by six weeks off dox.

Observed

Cytoplasmic inclusions of TDP-43 occur as early as one week off dox in neurons in the brain. Inclusions accumulate over time and are present in many brain regions, including the motor cortex. TDP-43 inclusions are relatively rare in the spinal cord. Ubiquitin-positive inclusions are also seen.

Observed

Astrogliosis develops in many brain regions, including layer V of the motor cortex.

Observed

Denervation of the hindlimb muscle tibialis anterior was detectable by four weeks off dox, that is, two weeks prior to detectable loss of lower motor neurons.

Observed

At end-stage, rNLS8 mice exhibit gross muscle atrophy of the hindlimb muscles tibialis anterior and gastrocnemius.

Observed

rNLS8 mice develop a variety of motor impairments, starting with a deficit in hindlimb clasping and a fine tremor in the forelimb and/or hindlimb. They also develop progressive loss of grip strength (as measured by the wire-hang test) and a progressive decline in coordinated movement and balance (as measured by the accelerating Rotarod).

Observed

Body mass peaked at approximately 7 weeks of age (i.e., two weeks off dox) and then progressively dropped. Excessive loss of body weight (>30% decrease from peak weight) often defined end-stage.

Observed

rNLS8 mice die prematurely. They reach end-stage 8-18 weeks off dox, with a median survival of 10.3 weeks off dox.

PFN1-C71G

Absent

No neuronal loss in the cortex but neurodegeneration in medulla.

Observed

By 4 months there was a loss of cervical motor neurons and an increase in degenerating axons.

Observed

Cytoplasmic inclusions of PFN1, ubiquitin, and p62 in motor neurons around 6 months.

Observed

Microgliosis and astrogliosis observed in the dorsal horn by 5 months.

Observed

Denervation of gastrocnemius muscle occurs by 5 months.

Observed

Muscle atrophy in lower hind limb occurs by 6 months.

Observed

By 4 months, mice began showing minor gate changes and at 5-6 months they began demonstrating progressive deficits in Rotorod performance, vertical behaviors, and grip strength. 

Observed

Body weight peaked at 4-6 months and then progressively decreased.

Observed

Mice were sacrificed when they were incapable of locomotion following the paralysis of two or more limbs which occurred around 7 months of age.

PrP-hFUS (R495X)

Absent

Not observed.

Absent

Not observed.

Absent

Despite high levels of cytoplasmic FUS, neuronal inclusions were not observed.

No Data

No data.

Observed

A number of abnormalities were detected in the hindlimb musculature by electromyography (EMG). These phenotypes were detectable by 8-12 months of age and included fibrillation potentials, muscle denervation, and a reduction in the number of motor units.

No Data

No data.

Absent

Not observed.

No Data

No data.

Observed

Hemizygous mice sporadically developed intestinal swelling leading to premature death (mean survival 118 days). Homozygous mice were more severely affected (50 percent of the original cohort died around 59 days of age).

PrP-hFUS (WT)

No Data

No data.

No Data

No data.

Absent

Not observed.

No Data

No data.

Absent

Not observed.

No Data

No data.

Absent

Not observed.

No Data

No data.

Observed

Hemizygous mice die prematurely following a brief illness characterized by poor feeding. Mean survival of hemizygotes ~203 days.

SOD1 (G37R)

Absent

Upper motor neuron loss was not observed, although vacuolization occurred in brainstem neurons.

Observed

Motor neurons in the spinal cord and brainstem degenerated with overt neuronal loss in the ventral horn in some regions of the spinal cord by 19 weeks. The degenerative process involved extensive vacuolization.

Absent

Not observed.

Observed

Astrogliosis occurs in the spinal cord by 11 weeks of age, becoming more severe with age.

Observed

Denervated endplates have been observed.

Observed

Loss of motor axons, denervated endplates, atrophy of muscle fibers, and fiber type grouping observed by end-stage.

Observed

Motor impairment at 4-6 months, beginning with reduced spontaneous movement, then tremors, limb weakness, and poor grooming. Eventual paralysis of the hindlimbs.

Observed

Loss of body weight is observed.

Observed

Mice survive about 6 to 8 months.

SOD1-G85R (hybrid)

No Data

Unknown.

Observed

Extensive degeneration of large spinal axons coincident with the onset of clinical symptoms. By end stage, motor neurons in the ventral horn are lost.

Observed

Astrocytic inclusions occur early, about 6 months of age. The inclusions are immunoreactive for SOD1 and ubiquitin.

Observed

Astrogliosis and microgliosis are observed in the spinal cord starting around 6.5 months of age, and become more severe with age.

Observed

Denervation of muscle fibers is observed.

Observed

Hemizygous mice develop muscle weakness around 9 months of age, coincident with atrophy and denervation of muscle fibers.

Observed

Progressive motor impairment generally starting around 8 months with reduced grip strength in one hindlimb, rapidly spreading to other limbs and leading to paralysis within about two weeks.

Observed

Hemizygous mice start to lose weight at about 9 months of age.

Observed

End stage is characterized by paralysis at about 10 months of age.

SOD1-G93A (hybrid) (G1H)

Observed

Although outright upper motor neuron loss is absent or rare, degenerative signs (e.g., swollen neurites, Gallyas-positive aggregates, vacuoles, and neuritic spheroids) have been shown in motor regions of the cerebral cortex by five months of age.

Observed

Up to 50% loss of motor neurons in the cervical and lumbar segments of the spinal cord at end stage.

Observed

Inclusions accumulate in spinal motor neurons starting around 82 days of age. Inclusions generally take the form of spheroids or Lewy-body-like inclusions and commonly include a variety of neuronal intermediate filament proteins. TDP-43-positive inclusions are not present.

Observed

Gliosis, including the proliferation of reactive microglia and astrocytes, develops in parallel with motor neuron degeneration in the spinal cord.

Observed

Neuromuscular junctions degenerate around 47 days of age; fast-fatiguable motor neurons are affected first.

Observed

Longitudinal MRI has shown reduced muscle volume as early as 8 weeks of age. Atrophy is progressive. Skeletal muscle is affected, including limb and diaphragm.

Observed

Signs of motor impairment begin at about 3 months of age with a shaking tremor that leads to paralysis.

Observed

One of the first signs of illness is a slowing of growth and a plateauing of weight.

Observed

G1H mice reach end-stage disease by 5 months of age. Females typically survive longer than males.

TARDBP (A315T) (congenic)

No Data

These mice lose corticospinal tract axons, but outright loss of cortical neurons has not been reported in the model. When crossed with a Thy-1YFP model to label layer 5 pyramidal neurons, mice expressing TDP-43 (A315T) had fewer neurons at 15 weeks of age than YFP littermate controls (Zhang et al., 2016).

Absent

Most studies reported no lower motor neuron loss. One study observed 20% loss of large ventral horn neurons, possibly dependent on diet and how long the mice live in an individual colony.

Observed

Ubiquitinated inclusions in the cytoplasm of spinal motor neurons and cortical layer V neurons. No evidence for cytoplasmic TDP-43 inclusions.

Observed

Reports of astrocytosis in cortical layer 5 and in the spinal cord, as well as microgliosis in the spinal cord.

Observed

Denervation of neuromuscular junctions at end stage (~11% on normal diet; ~20% loss on a gel diet).

Observed

Atrophy of gastrocnemius muscle (gel diet).

Observed

Deficits have been reported in nonspecific measures of strength and coordination such as the Rotarod (males and females) and hanging-wire test (males). A severely impaired gait (“swimming gait”) was observed in mice fed a gel diet.

Observed

Weight loss is a consistent feature. Potentially confounded by severe gut phenotype.

Observed

Survival is limited by severe gastrointestinal dysfunction and can be prolonged with a gel diet. Lifespan varies, but in general on a standard diet males live about 3 months and females about 6 months.

TARDBP (A315T) (hybrid)

Observed

By end-stage, neuronal numbers in layer 5 of the motor cortex are decreased with about 50 percent loss of corticospinal tract axons.

Observed

By end-stage, ~20% loss of motor neurons in the L3-L5 region of the spinal cord.

Observed

By end-stage, cytoplasmic inclusions of ubiquitinated proteins in layer 5 neurons of motor, sensory, and cingulate cortex. Ubiquitin aggregates in ventral horn neurons. TDP-43 inclusions were rare.

Observed

By end-stage, selective increase in GFAP immunoreactivity in cortical layer 5.

No Data

Unknown.

Observed

By end-stage, atrophic muscle fibers were observed.

Observed

Gait abnormalities around three months of age, developing into a characteristic “swimming gait” by four to five months.

Observed

Weight was comparable to non-Tg mice at birth. By 4.5 months transgenic mice began to lose weight.

Observed

Survival for about 5 months (154 ± 19 days) before dying spontaneously or being euthanized. It was not reported if this analysis includes males, females, or both.

Tardbp Q331K Knock-In

No Data

No data.

No Data

No data.

No Data

No data.

No Data

No data.

No Data

No data.

No Data

No data.

No Data

No data.

No Data

No data.

No Data

No data.

Tardp LCDmut

No Data

No data.

Observed

28 percent reduction in the number of motor neurons in the sciatic motor neuron pool, compared with non-transgenic littermates.

Observed

At 18 months of age, p62- and ubiquitin-positive inclusions are found in the ventral regions of the spinal cord, although these inclusions do not appear to be located in the cytoplasm of motor neurons.

No Data

No data.

Observed

By 24 months, a 15 percent reduction in motor units innervating the extensor digitorum muscle.

No Data

No data.

Observed

Grip strength in both male and female mice begins to decline at 12 months of age. By 24 months, there is a nearly 40 percent reduction in force measured in tibialis anterior muscles.

No Data

No data.

Absent

Do not exhibit premature death, at least until 24 months of age.

Tardp_RRM2mut

No Data

No data.

Absent

Not observed at 2 years.

Absent

Not observed at 2 years.

No Data

No data.

Absent

Not observed at 2 years.

No Data

No data.

Absent

Not observed at 2 years.

No Data

No data.

Absent

Homozygous mutation is embryonic lethal.

TDP-43 (A315T)

Absent

Not observed.

Absent

Not observed.

Observed

Cytoplasmic accumulation of TDP-43 was observed by 10 months of age in the spinal cord. Furthermore, cytoplasmic aggregates were observed and often co-localized with ubiquitin. These inclusions are not detected at three months of age.

Observed

Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.

No Data

Unknown.

No Data

Unknown.

Observed

At 38 weeks of age, mice develop impairments on the accelerating Rotarod relative to non-Tg littermates.

No Data

Unknown.

Absent

Not observed.

TDP-43 (A315T) (line 23)

Absent

Not observed.

Absent

Not observed.

Observed

Ubiquitin-positive cytoplasmic inclusions in neurons of the ventral horn and brainstem. Cytoplasmic aggregates of TDP-43 are largely absent, although rare phospho-TDP-43 inclusions were observed, especially at end-stage.

Observed

Mice exhibiting muscle weakness had astrocytosis in the ventral horn of the spinal cord.

No Data

Unknown.

Observed

Atrophy of muscle fibers in the quadriceps muscle of weak mice observed by day 44.

Observed

Progressive motor impairment, characterized by weakness, a decline in grip strength, and reduction in stride length. Weakness was usually more pronounced in the hindlimbs.

Observed

Progressive weight loss.

Observed

Line 23 mice survived about 2.5 months, mean survival 75 days. It was not reported whether this survival analysis includes males, females or both. Colony at Jackson Labs has longer mean survival.

TDP-43 (G348C)

Absent

Not observed.

Absent

Not observed.

Observed

Cytoplasmic accumulation of TDP-43 was observed by 10 months in the spinal cord. Cytoplasmic aggregates occurred and often co-localized with ubiquitin. These inclusions are not detected at 3 months of age.

Observed

Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.

Observed

In 10-month-old mice, approximately 10% of NMJs in the gastrocnemius muscle were denervated, with another 20% partially denervated.

No Data

Unknown.

Observed

Performance on the Rotarod was comparable to non-Tg littermates until 36 weeks of age, and became progressively worse with age.

No Data

Unknown.

Absent

Normal lifespan.

TDP-43 (M337V)

Absent

Not observed.

Absent

Not observed.

Observed

TDP-43 protein was largely nuclear, although some cytoplasmic TDP-43 was also observed. Some mild cytoplasmic inclusions were reported.

Observed

Reactive astrocytes and activated microglia proliferate in the spinal cord and brainstem.

No Data

No data.

No Data

No data.

Observed

Body tremors apparent by day 21 and the mice had difficulty recruiting their hindlimbs, leading to an irregular gait pattern, described as “dragging.”

 

Observed

By one month of age, homozygotes have reduced body weight compared to non-Tg littermates.

 

Observed

70% mortality of homozygotes by around one month of age.

TDP-43 (M337V) (Mt-TAR6/6)

Observed

Severe neuronal loss in all CA regions of the hippocampus of homozygous mice. Neuronal loss was also observed in layer V cortical neurons and thalamic neurons.

Observed

Neuronal loss was observed in the spinal cords of homozygous mice.

Observed

Some homozygous mice developed cytoplasmic inclusions in layer V cortical neurons. These were often, but not always, ubiquitin–positive. They were not universally observed, even in end-stage mice.

Observed

Elevated astrogliosis and microgliosis compared with non-Tg controls, especially in the motor cortex and spinal cord. Gliosis in the hippocampus was seen at end stage.

No Data

Unknown.

No Data

Unknown.

Observed

Motor impairment developed quickly, by 11 days of age in homozygous mice, starting with an abnormal clasping reflex. They also develop a hunched posture, muscle twitches, and reduced mobility. Paralysis developed within days, leading to death. Hemizygotes do not develop motor symptoms until about one year of age, and impairment varied from mouse to mouse.

Observed

Early postnatal growth retardation in homozygous mice. By day 17 their average body weight is about half that of non-Tg controls.

Observed

Homozygous mice survived an average of just 17 days. In contrast, hemizygous Mt-TAR6 mice lived up to 24 months (average survival ~16.4 months).

TDP-43 (Q331K)

No Data

Unknown.

Observed

Age-dependent loss of lower motor neurons in the lumbar spinal cord. Loss is detectable as early as 2 months of age and is more pronounced by 10 months.

Absent

TDP-43 in the brain and spinal cord was predominantly nuclear. Cytoplasmic TDP-43 aggregates were absent.

Observed

Elevated astrogliosis and microgliosis in the ventral horn of spinal cord by 10-12 months of age compared with non-Tg controls.

Observed

Reduction in neuromuscular junction endplates by 10-12 months of age. Remaining NMJs often had a “bleb-like” appearance.

No Data

Muscle fiber abnormalities including centralized nuclei and damage by 10-12 months of age.

Observed

Tremor, abnormal hindlimb clasping, impaired performance on the Rotarod were detectable starting around 3 months of age. Reduced grip strength occurred later.

No Data

Unknown.

No Data

Unknown.

TDP-43 (Q331K) Knock-In (Line 52)

Observed

25% loss of parvalbumin-positive neurons at 5 months.

Absent

Not observed.

Absent

Not observed.

No Data

Unknown.

Absent

Not observed.

No Data

Unknown.

Absent

Not observed.

Observed

Increased body weight.

Observed

Mutation may be deleterious to male embryos.

TDP-43 (WT) (Elliott)

Absent

Not observed.

Absent

Not observed.

Observed

Cytoplasmic ubiquitin-positive inclusions in skeletal muscle cells. Some TDP-43 inclusions, too.

No Data

No data.

No Data

No data.

Observed

An analysis of the quadriceps muscle, showed signs of myopathy, including variable muscle fiber size and disorganization of the muscle architecture.

Observed

Progressive motor impairment starting with external rotation of one hind limb followed by bilateral weakness and low muscle tone. Variable penetrance of this phenotype.

Observed

Progressive weight loss.

Observed

The mean survival of hemizygous mice was 109 days (it is not clear if this value represents males, females, or both).

TDP-43 (WT) (Julien model)

Absent

Not observed.

Absent

Not observed.

Absent

Primarily nuclear localization of human TDP-43.

Observed

Gliosis, both microgliosis and astrogliosis, occur early in the brain and spinal cord. Reactive glia were detected as early as 3 months of age, with more by 10 months.

Observed

Some NMJ denervation was observed by 10 months of age. About 5% of NMJs at the gastrocnemius muscle were denervated, with another 20 percent partially denervated.

No Data

No data.

Observed

Decreased performance on the accelerating Rotarod at 42 weeks of age. Further impairment at 52 weeks.

No Data

No data.

No Data

No data.

TDP-43 (WT) (Kumar-Singh)

Observed

In homozygous mice, quantitative loss of neurons occurs in the motor cortex compared with non-Tg littermates. Both superficial and deep cortical layers of the anterior cortex are affected.

Observed

By day 18, homozygous mice exhibited about 25 percent loss of motor neurons in the lumbar spinal cord compared with non-Tg littermates.

Observed

Homozygous mice developed cytoplasmic inclusions in the brain and spinal cord, many of which were ubiquitin-positive. A minority of inclusions co-labeled with TDP-43. Ultrastructural analysis revealed ubiquitin–negative cytoplasmic inclusions in anterior horn neurons to be abnormal accumulations of mitochondria.

Observed

Astrogliosis and microgliois especially in cortical layer V of the anterior cortex, including motor and somatosensory cortex, and in the spinal cord.

No Data

No data.

No Data

No data.

Observed

Homozygous mice exhibit an abnormal clasping reflex by postnatal day 14. Other early motor deficits include a shortened stride, a wide stance, and frequent stumbling. By day 18, reduced performance on the Rotarod. Complete paralysis occurs ~10 days after onset.

Observed

Size and weight of homozygous mice lag behind hemizygotes and non-Tg littermates.

Observed

Homozygous mice survive an average of just 24 days. In contrast, hemizygous mice survive to advanced age, although they die more prematurely than non-Tg mice, after 22 to 24 months.

TDP-43 (WT) (Petrucelli)

Absent

Not observed.

Absent

Neuronal loss was not detected in spinal cords of homozygous mice as assessed by TUNEL staining and caspase-3 staining.

Observed

Cytoplasmic eosinophilic aggregates in spinal motor neurons by one month of age in homozygous mice.

Observed

Astrogliosis and microgliosis in the anterior horn of the spinal cord by one month of age.

No Data

Unknown.

Absent

Atrophy of the gastrocnemius muscle was not observed.

Observed

By day 21, homozygous mice displayed body tremors and mild gait impairment which progressed into a “swimming gait” and severe motor impairment.

Observed

Homozygotes diverge early from non-Tg littermates in terms of body weight, showing significantly reduced weight gain.

 

Observed

Homozygous mice were sacrificed at one to two months of age when they were unable to right themselves.

TDP-43 (Wt-TAR6/6)

Observed

Approximate 15 percent loss of layer V neurons in motor cortex at 6 months.

Observed

Spinal motor neuron loss observed at 3 months, with approximately 10 percent fewer anterior horn neurons in lumbosacral regions at 6 months, compared with non-transgenic mice.

Observed

Inclusions containing phosphorylated TDP-43 rarely observed in the nuclei and cytoplasm of spinal neurons.

Observed

Microgliosis in cortex and spinal cord prominent at 6 months; astrogliosis in cortex and spinal cord apparent at 1.5 months.

No Data

No data.

Observed

Muscle wasting, particularly in flanks.

Observed

Progressive motor impairment; abnormal hind limb reflexes observed as early as 1.5 months.

Observed

TAR6/6 mice had lower body weights than non-transgenic mice between 3.25 and 3.75 months age, but the two genotypes were similar at younger and older ages (at least until 4.25 months).

Observed

Average survival is 6.7 months.

ΔNLS-FUS

Observed

By 1 year, there was neuronal loss in the motor cortex.

Absent

Not observed at 1 year in the L5 anterior horn.

Observed

Ubiquitin- and p62-positive ΔNLS-FUS inclusions in motor cortex neurons.  

Observed

Microgliosis and astrocytosis were observed in the motor cortex.

No Data

No data.

No Data

No data.

Observed

Progressive motor impairments by 12 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as decreased performance on the Rotarod and hanging wire tests.

Observed

Decreased by 48 weeks.

Observed

Approximately 50% mortality by 60 weeks of age.

ΔNLS-FUS x TDP-43(WT)

Observed

By 1 year, there was neuronal loss in the motor cortex.

Absent

Not observed at 1 year in the L5 anterior horn.

Observed

Ubiquitin- and p62-positive ΔNLS-FUS inclusions in motor cortex neurons.  

Observed

Microgliosis and astrocytosis were observed in the motor cortex.

No Data

No data.

No Data

No data.

Observed

Progressive motor impairments by 8 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as decreased performance on the Rotarod and hanging wire test.

Observed

Decreased by 48 weeks.

Observed

Approximately 40% mortality by 60 weeks of age.