Alzpedia

ABCA7

Synonyms: ATP-binding cassette, sub-family A, member 7

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ABCA7 is a member of the highly conserved superfamily of ATP-binding cassette (ABC) transporters. These multipass transmembrane proteins use energy from ATP hydrolysis to transfer molecules across membrane barriers. ABCA7 is abundantly expressed in white blood cells, in macrophages, and in microglia, where it is thought to play a role in phagocytosis. The ABCA7 gene started drawing attention in Alzheimer’s disease research when a genome-wide association study (GWAS) identified it as a risk factor for late-onset AD. Subsequent meta-analysis confirmed the association, and the gene ranks among the top 10 risk genes on AlzGene. The association is strongest for African-Americans, in whom one ABCA7 variant was found to nearly double the risk of AD, with an effect size approaching that of ApoE.

Despite the evidence linking ABCA7 to AD, the underlying mechanism of ABCA7’s role in AD pathogenesis remains unknown. ABCA7 could impact AD pathogenesis through a variety of mechanisms, including regulation of APP processing and clearance of Aβ through phagocytosis. Overall, the identification of ABCA7 as an AD risk factor further strengthens the importance of lipid homeostasis in the development of the disease.

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Alzpedia

BACE1

Synonyms: beta-secretase 1, beta-Site amyloid beta A4 precursor protein-cleaving enzyme, memapsin-2 (membrane-associated aspartic protease 2), aspartyl protease 2 (ASP2), HSPC104

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BACE1 encodes a transmembrane aspartyl protease responsible for β-secretase processing of the amyloid precursor protein (APP). APP cleavage by BACE1 is the rate-limiting step in the generation of Aβ peptides, creating the C99 fragment that becomes a substrate for subsequent γ-secretase cleavage. BACE1 is active in the acidic environment of early endosomes and trans-Golgi compartments, where Aβ is generated.

Its role in Aβ generation has made BACE1 a target for therapy development, and rational drug design efforts accelerated when the crystal structure of BACE was solved. A handful of BACE inhibitors have come to clinical trial, though some failed in Phase 1 due to safety concerns. BACE inhibitors are being watched for potential off-target effects of BACE1 inhibition, as the protease cleaves several dozen substrates. The best-studied is the cell surface protein neuregulin 1, whose soluble cleavage product signals through the receptor Erb4 on glial cells to regulate myelination. In addition, BACE1 is known to play a role in neurite outgrowth and muscle spindle formation. BACE knockout mice have mild schizophrenia-like and cognitive phenotypes.

The physiological function of APP processing by BACE1 remains unclear. The homolog BACE2 differs from BACE1 in its expression pattern and substrate specificity, and appears not to contribute significantly to Aβ generation.

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Alzpedia

ADAM10

Synonyms: ADAM-10, AD10, MADM, HsT18717, A Disintegrin and Metalloproteinase10, CD156c

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ADAM10 stands for A Disintegrin and Metalloproteinase 10. This membrane protein is a sheddase and thought to be the physiological α-secretase for the amyloid precursor protein (APP). In contrast to cleavage by β-secretase, ADAM10-mediated processing of APP is not amyloidogenic because cleavage takes place within the Aβ region, precluding Aβ generation. The proteolytic processing of APP by ADAM10 produces a secreted ectodomain fragment (sAPPα) that has neuroprotective and neurotrophic properties. For these reasons, increasing ADAM10 activity is viewed as potentially therapeutic for Alzheimer’s disease; however, pharmacological approaches have not yet succeeded.

Besides APP, physiological substrates of ADAM10 include Notch and various immune and growth factor proteins, and the protease itself can be processed into signaling molecules. ADAM10 influences neural development, neuroprotection, and synaptic physiology. Two rare mutations in ADAM10 have been associated with familial late-onset AD.

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Research Models

PS1 P264L

Synonyms: PS-1 P264L knock-in

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Species: Mouse
Genes: PSEN1
Modification: PSEN1: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A

Summary

Last Updated: 06 Mar 2018

COMMENTS / QUESTIONS

  1. Important clarification in an ongoing debate.

    View all comments by Benjamin Wolozin

  2. Very interesting knock-in transgenic mice models where neither APP nor PS were overexpressed.

    View all comments by Edward Koo

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Research Models

TgAPPSwe-KI

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Species: Mouse
Genes: APP
Modification: APP: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A

Summary

Last Updated: 25 Nov 2019

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Research Models

hBACE54

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Species: Mouse
Genes: BACE1
Modification: BACE1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A

Summary

Last Updated: 06 Mar 2018

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Research Models

Tau V337M

Synonyms: MAPT V337M, Tg214

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Species: Mouse
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia
Strain Name: N/A

Modification Details

Human 4-repeat tau driven by the PDGF-β promoter. Tagged with myc and Flag on the N- and C-terminals respectively.

Neuropathology

SDS-insoluble tau aggregates in hippocampus. Degenerating neurons in the hippocampus containing phosphorylated and ubiquitinated tau aggregates with β-sheet structure (Tanemura et al., 2002).

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

  • Gliosis
  • Synaptic Loss

Plaques

Absent.

Tangles

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

Synaptic Loss

Unknown.

Neuronal Loss

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

Gliosis

Unknown.

Changes in LTP/LTD

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

Cognitive Impairment

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

Last Updated: 06 Mar 2018

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Research Models

Tau R406W transgenic

Synonyms: TgTauR406W, Tau R406W-CAMKII

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Species: Mouse
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Frontotemporal Dementia, Alzheimer's Disease
Strain Name: N/A

Modification Details

Transgene containing human 4-repeat tau cDNA with the R406W mutation containing myc and FLAG tags at N-and C-terminal ends, respectively, and driven by the CaMK-II promoter.

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

  • Neuronal Loss
  • Gliosis
  • Synaptic Loss
  • Changes in LTP/LTD

Plaques

Absent.

Tangles

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

Synaptic Loss

Unknown.

Neuronal Loss

Unknown.

Gliosis

Unknown.

Changes in LTP/LTD

Unknown.

Cognitive Impairment

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

Last Updated: 06 Mar 2018

COMMENTS / QUESTIONS

  1. This work provides a valuable new model for familial tauopathies because it appears to provide important features lacking in other models. Specifically, these tau inclusions occur in the forebrain, unlike transgenic mice carrying P301L tau driven by the PrP promoter. Takashima has produced another transgenic tau mouse, however this new mouse appears to exhibit more robust pathology. Thus, this appears to be an excellent model of tauopathies.

    View all comments by Benjamin Wolozin

  2. This is an interesting paper describing an impressive animal model of tauopathy similar to that of AD. The strength of this model as compared to previous tau transgenic mice includes that (1) the specific promoter allowed the expression of the mutated tau mainly in cerebral cortex and hippocampus, producing tau pathology in these area, which is similar to AD and FTD; (2) the mutated tau expression was low so that the effect was specific rather than artifact merely due to many fold over-expression of any protein; and (3) the tau pathology caused some deficit in memory of the mice. The paper unfortunately didn't show whether the hyperphosphorylation occured only in mutant tau or mouse tau, or in both.

    View all comments by Cheng-Xin Gong

  3. Considerable progress is being made towards the development of novel and more effective therapeutic approaches for the treatment of Alzheimer's disease (AD) based on a design strategy to prevent or eliminate Aβ- deposits in fibrillar and non-fibrillar lesions in the brains of AD patients, and similar advances are rapidly evolving from efforts to reverse amyloid deposits in organs and tissues other than the brain in many of the systemic amyloidoses (1-3). The increasing realization that insights derived from therapeutic advances in one form of systemic or brain amyloidosis can be exploited to the benefit of treating other amyloidoses due the misfolding of many unrelated mutant and wild type proteins or peptides presents a powerful opportunity for ramping up the pace of progress in treating these disorders (3,4), many of which affect the elderly, the most rapidly increasing segment of the population in developed countries.

    While fibrillar Aβ deposits in the extracellular space known as senile plaques (SPs) and intraneuronal aggregates of tau fibrils known as neurofibrillary tangles (NFTs) are diagnostic amyloid lesions of AD, >50% of patients with familial or sporadic AD as well as elderly Down's syndrome (DS) patients with AD exhibit a third type of brain amyloid known as Lewy bodies (LBs) formed by intraneuronal accumulations of alpha-synuclein fibrils. Thus, AD is a "triple brain amlyloidosis" wherein at least three different building block proteins (tau, alpha-synuclein) or peptide fragments (Aβ) of a larger Aβ precursor protein (APP) fibrillize and aggregate into pathological deposits of amyloid within (NFTs, LBs) and outside (SPs) neurons. However, there are examples of other triple brain amyloidoses such as Down's syndrome (DS) and Mariana Island dementia or Guam Parkinson's-dementia Complex (Guam PDC) that also show evidence of accumulations of amyloid deposits formed by tau, alpha-synuclein and Aβ, and there is increasing recognition that tau or alpha-synuclein intraneuronal inclusions may converge with extracellular deposits of Aβ in "double brain amyloidoses" as exemplified by the co-occurrence of PD with abundant Aβ deposits and dementia, or PD with progressive supranuclear palsy in some patients.

    Significantly, the intraneuronal NFTs formed by aggregated tau filaments are similar to the filamentous tau inclusions characteristic of neurodegenerative tauopathies, many of which do not show other diagnostic disease specific lesions. Notably, tau gene mutations have been shown to cause familial frontotemporal dementia (FTD) and parkinsonism linked to chromosome 17 (FTDP-17) in many kindreds (5). Now, on line in PNAS, Tatebayashi et al. report another tau transgenic (TG) mouse that models aspects of FTDP-17 caused by the R406W tau gene mutation, and this TG mouse model not only includes prominent telencephalic NFTs, but also associative memory deficits linked to hippocampal accumulations of NFTs (6). The studies reported here on these TG mice add further evidence in support of the fact that tau pathology alone is wholly sufficient to cause neurodegenerative disease and they support a wealth of clinical data demonstrating tight correlations between progressive cognitive impairments and accumulations of cortical and hippocampal NFTs in AD. Although there have been many other reports describing a number of different tau TG mice, most have showed the most prominent tau amyloid burden in brainstem and spinal cord in association with a motor neuron disease like clinical phenotype (5). It is clear that multiple tau TG mouse model systems will be extremely helpful for developing new therapies to treat AD, FTDP-17, other FTDs, etc., and the significance of the PNAS paper by Tatebayashi et al. is that it provides a new model system of NFT pathology which is linked for the first time to cognitive impairments without sensory motor impairments based on the R406W tau mutation in FTDP-17. The model is of special importance because it can be exploited for drug discovery studies that target amelioration of tau amyloid induced memory impairments, as well as for elucidating mechanisms underlying the formation of one of the two major brain amyloids (i.e. tau amyloid) in AD as well as the similar types of tau amyloids that occur in familial and sporadic forms of FTD.

    Since many neurodegenerative diseases characterized by brain amyloidosis share an enigmatic symmetry such that missense mutations in the gene encoding the disease protein cause a familial variant of the disorder as well as its hallmark brain lesions, while the same brain lesions also form from the corresponding wild type brain protein in a sporadic variants of the disease, it is likely that clarification of this enigmatic symmetry in any one of these disorders will have a profound impact on understanding the mechanisms that underlie other of these brain amyloidoses as well as on efforts to develop novel therapies to treat them.

    John Q. Trojanowski, M.D., Ph.D.
    Director, Institute on Aging
    Director, Alzheimer's Disease Center
    Co-director, Center for Neurodegenerative Disease Research
    Department of Pathology and Laboratory Medicine
    University of Pennsylvania School of Medicine
    HUP, Maloney 3rd Floor
    36th and Spruce Streets
    Philadelphia, PA 19104-4283 USA
    Tel: 215-662-6399; Fax: 215-349-5909
    E-mail: trojanow@mail.med.upenn.edu

    Virginia M.-Y. Lee, Ph.D.
    Director, Center for Neurodegenerative Disease Research Department of Pathology and Laboratory Medicine
    University of Pennsylvania School of Medicine
    HUP, Maloney 3rd Floor
    36th and Spruce Streets
    Philadelphia, PA 19104-4283 USA
    Tel: 215-662-6427; Fax: 215-349-5909
    E-mail: vmylee@mail.med.upenn.edu

    References:

    Irizarry MC, Hyman BT. Alzheimer disease therapeutics. J Neuropathol Exp Neurol. 2001 Oct;60(10):923-8. PubMed.

    Mayeux R, Sano M. Treatment of Alzheimer's disease. N Engl J Med. 1999 Nov 25;341(22):1670-9. PubMed.

    Trojanowski JQ. "Emerging Alzheimer's disease therapies: focusing on the future". Neurobiol Aging. 2002 Nov-Dec;23(6):985-90. PubMed.

    Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei N, Ramponi G, Dobson CM, Stefani M. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature. 2002 Apr 4;416(6880):507-11. PubMed.

    Higuchi M, Lee VM, Trojanowski JQ. Tau and axonopathy in neurodegenerative disorders. Neuromolecular Med. 2002;2(2):131-50. PubMed.

    Tatebayashi Y, Miyasaka T, Chui DH, Akagi T, Mishima K, Iwasaki K, Fujiwara M, Tanemura K, Murayama M, Ishiguro K, Planel E, Sato S, Hashikawa T, Takashima A. Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13896-901. PubMed.

    View all comments by John Trojanowski

  4. This is a laudable effort to generate and characterize a mouse model for an
    FTD-related pathology. By expressing the human tau[R406W] FTD-mutant using the
    CaMKII-promoter, the mice express the human mutant tau protein at a rather low
    level (20% of endogenous) and mainly in neurons in forebrain - not or hardly
    in cerebellum, brain stem or spinal cord. This outcome clearly prevents and
    circumvents the motoric problems that we and others have observed and described
    in transgenic mice that express wild-type or mutant protein tau using a more
    widely expressing promoter, i.e. the mouse thy-1 gene promoter.

    The tau[R406W] mice develop at old age (> 18 to 23 months) a neuro-pathology
    that is best characterized by intra-neuronal accumulations of protein tau, resulting
    in "deformed" cell-shape with largely absent micro-tubules and formation of
    filamentous tau-aggregates. The morphological characteristics of the cells and
    aggregates are reminiscent of what is observed in brain of certain human patients.
    The mice appear to develop "mixed" tau-aggregates, i.e. containing mouse and
    human tau, although neither their biochemical characterization nor the quality
    of the EM pictures presented in this report are completely convincing of their
    exact nature and precise characteristics. The eventual formation of straight
    filaments in old Tg mice is documented, but these are actually unlike those
    observed in the brain of FTD [R406W] patients ! This is another indication that
    we do not understand the structural nor (patho)-physiological driving forces
    behind the tau-pathology in FTD - nor in AD for that matter.

    Technically I am somewhat concerned about the fact that the transgenic human
    tau protein is tagged at both ends with different markers, i.e. myc and FLAG,
    despite the availability of excellent antibodies against human and mouse protein
    tau. This might indeed affect the actual formation, kinetically and structurally,
    of the aggregates.

    The study remains overall rather descriptive and would have been served by
    a quantitative analysis of the actual pathology - a point also raised by the
    authors in their discussion. The data do not allow one to appreciate the regional
    aspects nor the extent of the pathology throughout the hippocampus and the forebrain.
    One is left wondering about the earliest signs and age of onset and the associated
    individual mouse-to-mouse variability, that is known and evident in other transgenic
    mouse models - whether tau or amyloid related.

    The behavioral analysis is on the other hand well represented in "caught in
    numbers", to prove that tau[R406W] mice have normal sensorimotor functions and
    appear also emotionally not deficient. The defects in associative memory as
    demonstrated by cued and contextual fear-conditioning tests are robust despite
    the authors' own statement in the discussion that "... appearance of tau inclusions
    in aged Tg mice is variable." One cannot but interpret this to mean that not
    the inclusions per se are responsible - but rather "something else". Clearly,
    this is more than reminiscent of the transgenic mouse amyloid models, in which
    the current view is - finally - turning to the "pre-amyloid deposition phases"
    to explain defects and observations that are not directly related to deposition
    per se. Hopefully "the chase for mice with amyloid plaques" will not be duplicated
    as "the chase for mice with PHF and NFT" to prevent other hypotheses to emerge
    - other than those heralding "deposition" as the one and only pathological mechanism
    in neurodegeneration.

    View all comments by Fred Van Leuven

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Further Reading

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Research Models

hBACE

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Species: Mouse
Genes: BACE1
Modification: BACE1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A

Summary

Last Updated: 06 Mar 2018

COMMENTS / QUESTIONS

  1. EB Lee and colleagues provide very interesting data indicating that
    high BACE overexpression paradoxically reduces Aβ levels and
    plaque pathology in Tg2576 transgenic mice harboring the APP Swedish
    mutation. They employ diverse methods to demonstrate that BACE
    overexpression reduces transport of mature and phosphorylated APP
    into axons. This publication underscores the importance of studying AD
    biology in neurons, especially their processes. Increasing evidence is
    placing the critical site of Aβ generation, and accumulation,
    within neurites and synapses. Disruption of the perforant path has
    previously been shown to reduce plaque pathology in synaptic terminal
    fields of the hippocampus. Aβ at synapses may even have a
    physiological role that as yet is poorly defined. A central but more
    controversial issue is how Aβ generation at synapses links to
    synaptic dysfunction and plaque formation.

    A topic not discussed in the paper is the growing literature on intraneuronal Aβ
    accumulation with AD pathogenesis. Indeed, the labs of Virginia Lee
    and John Trojanowski were pioneers in studies on intracellular Aβ.
    Their work raises the intriguing question of why the low BACE
    expressing APP mutant mice have reduced plaques in hippocampus but
    increased plaques in cortex. The authors speculate that differential
    effects of increased BACE in projection neurons with long axons
    compared to smaller interneurons with shorter axons may be involved.
    Despite the emphasis on axons and presynaptic compartments, one could
    also consider the potential involvement of dendrites and postsynaptic
    compartments, which are more difficult to study but also accumulate
    Aβ. Overall, this is exciting new work using rigorous analysis of
    APP/Aβ processing with elegant in vivo experiments that provide
    novel insights into the neurobiology of AD.

    View all comments by Gunnar Gouras

  2. I agree with Martin and Gouras that this paper deserves serious study since it is an ambitious attempt to explore whether cleavage of APP at different subcellular sites determines whether Abeta peptides are ultimately toxic to the neurons in which the are produced.

    The authors found that increased expression of beta secretase in mice has a paradoxical effect on Aβ levels and plaque development. High levels of beta secretase decrease Aβ levels and retard plaque formation, contrary to what might have been predicted. They propose that excessive beta secretase cleaves APP prematurely in the ER/Golgi regions of neurons, thereby reducing their translocation to distal segments where it is presumed that abeta peptides might be more toxic. While this is an interesting idea, I would look for deeper explanations.

    Other interesting effects are also described, such as a striking decrease in levels of phosphorylated C99, a product of beta cleavage, while non-phosphorylated C99 and other amino terminal fragments of APP accumulate inside cells. This makes one wonder whether high levels of beta secretase, or the peptides they generate, have as yet unsuspected actions that might influence other metabolic pathways including kinase/phosphatase actions and the PS1/gamma secretase complex.

    View all comments by Vincent Marchesi

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Research Models

APP751SL/PS1 KI

Synonyms: APP(SL)PS1KI, APPxPS1-Ki, APPSL/PS1KI, APP(SL)/PS1(KI), APP/PS1KI

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Species: Mouse
Genes: APP, PSEN1
Modification: APP: Transgenic; PSEN1: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A

Modification Details

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 (Blanchard et al., 2003).

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

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).

Tangles

Absent.

Synaptic Loss

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

Neuronal Loss

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).

Gliosis

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

Changes in LTP/LTD

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).

Cognitive Impairment

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).

Last Updated: 25 Nov 2019

COMMENTS / QUESTIONS

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Further Reading

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