Formation of Filamentous Tau Aggregations in Transgenic Mice Expressing V337M Human Tau

Tanemura, Kentaro; Akagi, Tomonori; Murayama, Miyuki; Kikuchi, Noriko; Murayama, Ohoshi; Hashikawa, Tsutomu; Yoshiike, Yuji; Park, Sungha; Matsuda, Keiko; Nakao, Shinobu; Sun, Xiaoyan; Sato, Shinji; Yamaguchi, Hideyo; Takashima, Akihiko

doi:10.1006/nbdi.2001.0439

Cited by 133 publications

(68 citation statements)

References 24 publications

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“…A fluorescent microscope equipped with a cooled CCD camera and Neurolucida software (Version 7; MicroBrightField Inc., Williston, VT) were used to analyze the sections and for acquisition of images under virtual slice mode. NFTs were identified by means of the standard Gallyas silver-impregnation method (10).…”

Section: Methodsmentioning

confidence: 99%

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Aggregation of Detergent-insoluble Tau Is Involved in Neuronal Loss but Not in Synaptic Loss

Kimura

Fukuda

Sahara

et al. 2010

Journal of Biological Chemistry

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101

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Neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau, are hallmarks of neurodegenerative diseases including Alzheimer disease (AD). In neurodegenerative diseases, neuronal dysfunction due to neuronal loss and synaptic loss accompanies NFT formation, suggesting that a process associated with NFT formation may be involved in neuronal dysfunction. To clarify the relationship between the tau aggregation process and synapse and neuronal loss, we compared two lines of mice expressing human tau with or without an aggregation-prone P301L mutation. P301L tau transgenic (Tg) mice exhibited neuronal loss and produced sarcosyl-insoluble tau in old age but did not exhibit synaptic loss and memory impairment. By contrast, wild-type tau Tg mice neither exhibited neuronal loss nor produced sarcosyl-insoluble tau but did exhibit synaptic loss and memory impairment. Moreover, P301L tau was less phosphorylated than wild-type tau, suggesting that the tau phosphorylation state is involved in synaptic loss, whereas the tau aggregation state is involved in neuronal loss. Finally, increasing concentrations of insoluble tau aggregates leads to the formation of fibrillar tau, which causes NFTs to form. NFTs2 are commonly observed in neurodegenerative disorders. Brain regions containing NFTs also exhibit neuronal loss. The rate of neuron loss is much greater than the rate of NFT formation, suggesting that NFT formation and neuronal death share a common mechanism (1, 2). This hypothesis is strongly supported by the discovery of tau gene mutations in individuals with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) (3, 4). A single tau gene mutation induces NFT formation and neuronal loss with 100% penetration. Moreover, overexpression of human FTDP-17 tau induces NFT formation, neuronal loss, and behavioral deficits in mice (5-12).Mice that overexpress P301L mutant tau under the regulation of a tetracycline-inducible promoter display age-related NFTs, neuronal death, and behavioral deficits (13,14). Although inhibiting mutant tau overexpression in these mice blocks neuronal death and improves memory, NFTs continue to form (13,15). This suggests that NFTs are not themselves toxic but, instead, that NFT formation and neuronal death and neuronal dysfunction share a common underlying mechanism.The P301L tau mutation is known as an "aggregation-prone mutation" in that individuals harboring this mutation produce mutant tau that readily aggregates (16 -18). The NFTs of one patient with an aggressive FTDP-17 phenotype consisted of only P301L mutant tau (19), indicating that P301L mutant tau itself may possess a toxic function by forming aggregated tau.The formation of tau fibrils is believed to involve three sequential steps (20,21). First, monomeric tau binds together to form oligomers that are soluble in sarcosyl solution. The structure of these oligomers, however, is not discernible under atomic force microscopy. Second, as soluble tau oligomers take on a ␤-sheet structure, they form tau aggregat...

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Section: Methodsmentioning

confidence: 99%

“…A single tau gene mutation induces NFT formation and neuronal loss with 100% penetration. Moreover, overexpression of human FTDP-17 tau induces NFT formation, neuronal loss, and behavioral deficits in mice (5)(6)(7)(8)(9)(10)(11)(12).…”

Section: Nftsmentioning

confidence: 99%

Aggregation of Detergent-insoluble Tau Is Involved in Neuronal Loss but Not in Synaptic Loss

Kimura

Fukuda

Sahara

et al. 2010

Journal of Biological Chemistry

Self Cite

101

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“…Surprisingly, none of these plaque producing transgenic models display NFTs or ADtype neurodegenerative changes (Van Leuven, 2000), suggesting that additional mechanisms underlie AD. Although NFTs are seen in independent transgenic models overexpressing mutant tau isoforms, which are linked to tauopathies in humans (Lewis et al, 2000;Gotz et al, 2001;Tanemura et al, 2001;Tatebayashi et al, 2002), there are no known tau mutations associated with AD.…”

Section: Introductionmentioning

confidence: 99%

Conditional Neuronal Simian Virus 40 T Antigen Expression Induces Alzheimer-Like Tau and Amyloid Pathology in Mice

Park¹,

Hallows²,

Chakrabarty³

et al. 2007

J. Neurosci.

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A large body of evidence has shown the activation of a cohort of cell cycle regulators and the duplication of DNA in degenerating neurons of Alzheimer's disease (AD) brain. Activation of these regulators and duplication of chromosomes precede neurodegeneration and formation of neurofibrillary tangles (NFTs), one of the diagnostic lesions of AD. These findings, in combination with evidence for cell cycle regulation of amyloid precursor protein and tau, has led to the hypothesis that reentry into the cell cycle underlies AD pathogenesis. To test this hypothesis directly, we have created transgenic mice with forced cell cycle activation in postmitotic neurons via conditional expression of the simian virus 40 large T antigen (TAg) oncogene. We show that TAg mice recapitulate the cell cycle changes seen in AD and display a neurodegenerative phenotype accompanied by tau pathology and NFT-like profiles. Moreover, plaque-like amyloid deposits, similar to those seen in AD, are also observed in the brains of TAg mice. These data provide support for an essential role of ectopic cell cycle activation in the generation of the characteristic pathological hallmarks of AD. Furthermore, our TAg mice are the first model to develop NFTs and amyloid pathology simultaneously and in the absence of any human transgenes. These mice will be useful for further defining the nongenetic mechanisms in AD pathogenesis and for the development of cell cycle-based therapies for AD.

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“…TauV337M [52]: Mice express low level synthesis of 4R MAPT with the V337M mutation (1/10 of endogenous mouse MAPT) driven by the promoter of platelet-derived growth factor (PDGF). The development of neurofibrillary pathology in these mice suggests the nature of tau rather than absolute intracellular tau concentrations drives pathology.…”

Section: Bri-a 40 and Bri-a 42mentioning

confidence: 99%

Prospects for Early Detection of Alzheimers Disease from Serial MR Images in Transgenic Mouse Models

Muskulus¹,

Scheenstra²,

Braakman³

et al. 2009

CAR

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Abstract:The existing literature on the magnetic resonance imaging of murine models of Alzheimer's disease is reviewed. Particular attention is paid to the possibilities for the early detection of the disease. To this effect, not only are relaxometric and volumetric approaches discussed, but also mathematical models for plaque distribution and aggregation. Image analysis plays a prominent role in this line of research, as stochastic image models and texture analysis have shown some success in the classification of subjects affected by Alzheimer's disease. It is concluded that relaxometric approaches seem to be a promising candidate for the task at hand, especially when combined with sophisticated image analysis, and when data from more than one time-point is available. There have been few longitudinal studies of mice models so far, so this direction of research warrants future efforts.

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Formation of Filamentous Tau Aggregations in Transgenic Mice Expressing V337M Human Tau

Cited by 133 publications

References 24 publications

Aggregation of Detergent-insoluble Tau Is Involved in Neuronal Loss but Not in Synaptic Loss

Aggregation of Detergent-insoluble Tau Is Involved in Neuronal Loss but Not in Synaptic Loss

Conditional Neuronal Simian Virus 40 T Antigen Expression Induces Alzheimer-Like Tau and Amyloid Pathology in Mice

Prospects for Early Detection of Alzheimers Disease from Serial MR Images in Transgenic Mouse Models

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