. 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.

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  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.

  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.

  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.

    References:
    1. Irizarry MC, Hyman BT. Alzheimer disease therapeutics. J Neuropath Exper
    Neurol, 60:923-928, 2001. Abstract
    2. Mayeux R, Sano M. Treatment of Alzheimer's disease. New Engl J Med, 341:1670-1679,
    1999. Abstract
    3. Trojanowski JQ. Emerging Alzheimer's disease therapies: Focusing on the future.
    Neurobiol Aging, In press, 2002.
    4. Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, Taddei
    N, Ramponi G, Dobson C, Stefani M. Inherent toxicity of aggregates implies a
    common mechanism of protein misfolding disease. Nature, 416:507-511, 2002. Abstract
    5. Higuchi M, Lee VM-Y, Trojanowski JQ. Tau and axonopathy in neurodegenerative
    disease. NeuroMolec Med, In press, 2002.
    6. Tatebayashi Y, Miyasaka T, Chui, D.-H., Akagi T, Mishima K-I, Iwasaki K,
    Fujiwara M, Tanemura K, Murayama M, Ishiguro K, Planel E, Sata S, Hashikawa
    Takashima A. Tau filament formation and associative memory deficit in aged mice
    expressing mutant (R406W) human tau. PNAS USA, In press, 2002.

    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
    http://www.uphs.upenn.edu/aging/

    http://www.med.upenn.edu/ADC
    http://www.uphs.upenn.edu/cndr/

    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

    http://www.uphs.upenn.edu/cndr/

  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.

This paper appears in the following:

Research Models

  1. TAU R406W