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

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

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...  Read more

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/

View all comments by John Trojanowski

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"...  Read more

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