Research Models

APP(Swedish) (R1.40)

Synonyms: APPK670/M671, R1.40-YAC

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Species: Mouse
Genes: APP
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6.129-Tg(APPSw)40Btla/Mmjax

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Tangles
  • Changes in LTP/LTD

No Data

  • Neuronal Loss
  • Synaptic Loss
  • Cognitive Impairment

Plaques

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

Tangles

No mature tangles, but some changes in phosphorylated tau.

Synaptic Loss

Unknown.

Neuronal Loss

Unknown.

Gliosis

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

Changes in LTP/LTD

Absent.

Cognitive Impairment

Unknown.

Last Updated: 25 Nov 2019

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Further Reading

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Research Models

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

Synonyms: APPSwDI

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Species: Mouse
Genes: APP
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease, Cerebral Amyloid Angiopathy, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type
Strain Name: C57BL/6-Tg(Thy1-APPSwDutIowa)BWevn/Mmjax

Neuropathology

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Tangles

No Data

  • Neuronal Loss
  • Synaptic Loss

Plaques

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

Tangles

Absent.

Synaptic Loss

Unknown.

Neuronal Loss

Unknown.

Gliosis

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

Cognitive Impairment

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

Last Updated: 31 Jan 2025

COMMENTS / QUESTIONS

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Further Reading

No Available Further Reading

Research Models

rTg(tauP301L)4510

Synonyms: rTg4510, rTg(tetO-TauP301L)4510, Tau P301L

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Species: Mouse
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia
Strain Name: 129S6.Cg-Tg(Camk2a-tTA)1Mmay/JlwsJ; Fgf14Tg(tetO-MAPT*P301L)4510Kha/J. Formerly: 129S6.Cg-Tg(Camk2a-tTA)1Mmay/JlwsJ; FVB-Tg(tetO-MAPT*P301L)#Kha/JlwsJ

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Plaques

No Data

  • Changes in LTP/LTD

Plaques

Absent.

Tangles

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

Synaptic Loss

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

Neuronal Loss

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

Changes in LTP/LTD

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

Cognitive Impairment

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

Last Updated: 17 Jul 2019

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Further Reading

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Research Models

Tau P301S (Line PS19)

Synonyms: PS19Tg

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Species: Mouse
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia
Strain Name: B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle/J

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Plaques

No Data

Plaques

Absent.

Tangles

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

Synaptic Loss

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

Neuronal Loss

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

Gliosis

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

Changes in LTP/LTD

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

Cognitive Impairment

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

Last Updated: 13 Apr 2018

Further Reading

No Available Further Reading

Research Models

APPswe/PSEN1dE9 (line 85)

Synonyms: APP/PS1, APPswe/PS1deltaE9, line 85, APP(swe) + PSEN1DeltaE9, APPdE9, Borchelt mice

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Species: Mouse
Genes: APP, PSEN1
Mutations: PSEN1: deltaE9
Modification: APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Tangles

No Data

Plaques

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).

Tangles

Not observed.

Synaptic Loss

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).

Neuronal Loss

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

Gliosis

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).

Changes in LTP/LTD

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).

Cognitive Impairment

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).

Last Updated: 08 Oct 2019

COMMENTS / QUESTIONS

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Further Reading

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Alzpedia

TDP-43

Synonyms: TAR DNA-binding protein 43, TDP43, TARDBP, ALS10, transactive response DNA-binding protein of 43 kDa

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In 2006, TAR DNA-binding protein 43 (TDP-43) was identified as the cardinal protein in the most common subtypes of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Together with the 2006 discovery of progranulin, this was a major breakthrough in the study of FTD.

TDP-43 is a widely expressed nuclear protein that binds both DNA and RNA. While shuttling between nucleus and cytoplasm, it helps regulate many aspects of RNA processing, such as splicing, trafficking, stabilization, and miRNA production. For example, TDP-43 affects RNAs that encode proteins involved in autophagy and other cellular protein homeostasis and clearance pathways. A role in axonal transport has also been proposed. In neurodegenerative diseases, neuronal and glial TDP-43 becomes mislocalized to the cytoplasm, where it aggregates into stress granules and insoluble inclusion bodies. These inclusions occur in all people with FTD or ALS caused by mutations in C9ORF72, progranulin, valosin-containing protein, or TDP-43 itself, as well as in some familial cases of unknown mutation and some sporadic cases, and in about a quarter of Alzheimer’s disease cases.

Regardless of the proximal cause of a given patient’s disease, distribution of TDP-43 pathology tends to correlate with brain areas of atrophy and the stage of dementia, hence TDP-43 dysregulation is considered to reflect a common downstream mechanism of neurodegeneration. A staging scheme to classify TDP pathology at autopsy has been proposed. Whether the inclusions themselves or soluble species are toxic remains unclear.

TDP-43 protein is 96 percent identical between human and mice, and more than a dozen knockout and transgenic lines of wild-type and mutant TDP-43 have been created. Most reflect some pathologic features of ALS/FTD but not the corresponding functional deficits; brain-specific conditional models may be required. Zebrafish, fruit fly, worm, and human induced pluripotent stem cell models exist as well, and are used in efforts to define the protein’s role in the pathogenesis of these diseases.

Further Reading

No Available Further Reading

Alzpedia

SORLA (SORL1)

Synonyms: Sorting protein-related receptor containing LDLR class-A repeats, Sortilin-related receptor, SORLA1, LR11, LRP9, gp250, C11orf32

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The sortilin-related receptor SORLA is an endocytic receptor that belongs to the vacuolar protein sorting 10 (VPS10) domain receptor family. SORLA binds to the amyloid precursor protein (APP). It functions as an intracellular sorting receptor as APP is being trafficked between the secretory pathway, the cell surface, and, subsequently, endosomes. SORLA is localized primarily to the trans-Golgi network and early endosomes, shuttling between these two membrane compartments. SORLA’s interaction with APP in endosomal compartments limits the amyloidogenic proteolysis of APP. Reduced brain levels of SORLA are thought to alter the transport and processing of APP to increase generation of Aβ peptides in early or late endosomes.

SORLA is highly expressed in the brain. Expression is reported to be normal in familial Alzheimer's disease caused by mutations in presenilin or APP genes, but decreased in some cases of sporadic late-onset AD. In these cases, loss of SORLA activity has been hypothesized to be a proximal cause of amyloidosis. In addition, several private nonsense and missense mutations in SORLA that decrease SORLA levels in the brain were found in rare cases of familial AD.

A genetic association of SORLA with AD is well established. Population-based studies initially linked nearly 30 SNPs in SORLA to increased risk of AD, and subsequent studies, meta-analyses, and GWAS have confirmed some of these associations. The genetic data on SORLA and LOAD is complex, with at least six different polymorphisms pointing toward the existence of several causative variants in distinct regions of the gene.

Several SORLA variants associated with AD have been reported to result in reduced SORLA protein levels, though overall regulation of SORLA expression is only partially understood. CSF biomarker studies of SORLA are inconclusive, with some but not all studies showing reduction in LOAD.

In addition to being a sorting receptor, SORLA has structural features of lipoprotein receptors, particularly the low-density lipoprotein (LDL) receptor family. It therefore may affect AD risk through its effects on lipoprotein signaling pathways, especially those involving the LDLR ligand apolipoprotein E. Besides ApoE, ligands that interact with SORLA’s extracellular portion include the growth factors GDNF and BDNF; however, the relevance, if any, of this binding to AD is unknown.

As a type-1 transmembrane protein, SORLA can undergo regulated intramembrane proteolysis and in the process shed a soluble ectodomain, but the physiological relevance of this fragment is unclear.

Further Reading

No Available Further Reading

Alzpedia

TREM2

Synonyms: Triggering receptor expressed on myeloid cells 2, Trem2a, Trem2b, Trem2c, TREM-2

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Triggering receptor expressed on myeloid cells 2 (TREM2) is a receptor of the innate immune system expressed on microglia, macrophages, dendritic cells, and osteoclasts. TREM2 is a member of the immunoglobulin superfamily. Endogenous ligands of this receptor are unknown but when triggered, it signals through the transmembrane adapter protein TYROBP/DAP12 to activate phagocytosis of pathogens and cellular debris. Anti-inflammatory properties of TREM2 have also been described, whereby TREM2 supresses expression and secretion of inflammatory cytokines in macrophages and microglia.

In 2012, functional variants of TREM2 were associated with late-onset Alzheimer’s disease and frontotemporal dementia. The R47H variant in particular was reported to nearly triple the risk of AD, although the exact genetic burden of this and other TREM2 variants requires further research. Autosomal recessive mutations in TREM2 cause Nasu-Hakola disease; this rare genetic disorder of bone abnormalities and progressive dementia is fatal by mid-life.

Preliminary evidence suggests that TREM2 may affect AD pathogenesis via amyloid-related neuroinflammation and via phagocytosis of amyloid and neuronal debris. Of note, however, patients with Nasu-Hakola disease who lack TREM2 develop no plaque pathology. Network analysis of gene expression data in AD-relevant brain regions, including the hippocampus, has identified TREM2 as a regulatory hub that connects to other genes implicated in Alzheimer’s and related diseases. Although the exact pathological mechanisms remain to be worked out, the association of TREM2 and AD underscores the importance of innate immunity and microglial activity in neurodegeneration.

Further Reading

No Available Further Reading

Alzpedia

PICALM

Synonyms: phosphatidylinositol binding clathrin assembly protein, clathrin assembly lymphoid-myeloid leukemia (CALM) protein, LAP, CLTH

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PICALM is an accessory protein in the endocytic pathway. Ubiquitously expressed, PICALM binds to clathrin and its adaptor proteins, which together regulate the formation of the clathrin lattice during endocytosis. PICALM was identified in one of the first large-scale genome-wide association studies (GWAS) for late-onset Alzheimer’s disease and remains one of the top 10 risk genes on AlzGene. Multiple single nucleotide polymorphisms (SNPs) within and around the PICALM gene have been associated with AD; however, the pathogenic variant(s) and the underlying mechanisms by which they affect a person’s risk of AD remain unknown.

PICALM is involved in many cellular processes, with many opportunities to influence AD pathogenesis. A prominent hypothesis holds that it affects internalization of APP and thus the production of Aβ. Additionally, PICALM could act through effects on the endocytosis and trafficking of other molecules important for neuronal function.

Further Reading

No Available Further Reading

Alzpedia

Complement Receptor 1 (CR1)

Synonyms: Complement component (3b/4b) receptor 1, CD35 antigen, C3b/C4b receptor, C3-binding protein, Knops blood group antigen

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The complement receptor 1 (CR1) gene encodes a transmembrane glycoprotein that functions in the innate immune system. CR1 is expressed on blood cells and microglia. As a receptor for the complement components C3b and C4b, CR1 helps regulate activation of the complement cascade and promotes phagocytosis of immune complexes and cellular debris, as well as Aβ. CR1 attracted attention in Alzheimer’s research when variants at the CR1 locus proved to be associated with risk of late-onset Alzheimer’s disease. Meta-analysis has confirmed several disease-associated single nucleotide polymorphisms (SNPs), as well as a copy-number variation (CNV). CR1 currently ranks among the top 10 risk genes on AlzGene. At least one risk SNP is also linked to intracerebral hemorrhage associated with cerebral amyloid angiopathy (CAA).

While the molecular underpinnings of CR1’s role in AD pathogenesis are not yet clear, accumulating evidence suggests a dysregulation of complement with effects on inflammation and amyloid accumulation. Clinically, a CR1 risk allele has been associated with faster cognitive decline and greater neuropathology burden in longitudinal aging cohorts. 

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