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67 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 (67)
<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. The parental origin of the transgenes has been shown to influence plaque burdens in 5xFAD mice on a C57BL6 background—with plaque burdens higher in mice who inherited the APP and PSEN1 transgenes from their fathers, compared with those who inherited the transgenes from their mothers. 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
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>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
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
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-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>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>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>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
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>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
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
<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
<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
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>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
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
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
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>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
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>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>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
<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 (Volga) 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
<p>PS2(N141I) x APPswe</p>, <p>hPS2(N141I) x hAPPswe</p> 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 (Volga) 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
<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
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
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
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>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
<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 (Volga) 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
<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
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>-</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
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-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>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
<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>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
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

64 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 23

    Neuron loss in cortical layer V and subiculum.

  3. X
    Gliosis at 9

    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 25

    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. Amyloidosis more severe in females than males.

  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

    LTD was induced in layer V cortical neurons of 8- to 10-week-old 5xFAD mice using the same protocol that induced spike-timing-dependent LTP in neurons of non-transgenic mice. LTP at Schaffer collateral-CA1 synapses was decreased in 5xFAD by 4 months of age.

  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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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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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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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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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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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/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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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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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(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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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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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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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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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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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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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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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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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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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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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 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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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 (Volga) 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 (Volga) 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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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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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/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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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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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 (Volga) 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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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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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 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-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) 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 (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 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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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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