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論文
タイトル
タイトル(英)
Development of a novel tau propagation mouse model endogenously expressing 3 and 4 repeat tau isoforms.
参照URL
https://researchmap.jp/masatohasegawa/published_papers/35110892
著者
著者(英)
Masato Hosokawa,Masami Masuda-Suzukake,Hiroshi Shitara,Aki Shimozawa,Genjiro Suzuki,Hiromi Kondo,Takashi Nonaka,William Campbell,Tetsuaki Arai,Masato Hasegawa
概要
概要(英)
The phenomenon of "prion-like propagation" in which aggregates of abnormal amyloid-fibrilized protein propagate between neurons and spread pathology, is attracting attention as a new mechanism in neurodegenerative diseases. There is a strong correlation between the accumulation or spread of abnormal tau aggregates and the clinical symptoms of tauopathies. Microtubule-associated protein of tau contains a microtubule-binding domain which consists of 3-repeats or 4-repeats due to alternative mRNA splicing of transcripts for the Microtubule-associated protein of tau gene. Although a number of models for tau propagation have been reported, most utilize 4-repeat human tau transgenic mice or adult wild-type mice expressing only endogenous 4-repeat tau and these models have not been able to reproduce the pathology of Alzheimer's disease in which 3-repeat and 4-repeat tau accumulate simultaneously, or that of Pick's disease in which only 3-repeat tau is aggregated. These deficiencies may reflect differences between human and rodent tau isoforms in the brain. To overcome this problem, we used genome editing techniques to generate mice that express an equal ratio of endogenous 3-repeat and 4-repeat tau, even after they become adults. We injected these mice with sarkosyl-insoluble fractions derived from the brains of human tauopathy patients such as those afflicted with Alzheimer's disease (3- and 4-repeat tauopathy), corticobasal degeneration (4-repeat tauopathy) or Pick's disease (3-repeat tauopathy). At 8-9 months following intracerebral injection of mice, histopathological and biochemical analyses revealed that the abnormal accumulation of tau was seed-dependent, with 3- and 4-repeat tau in Alzheimer's disease-injected brains, 4-repeat tau only in corticobasal degeneration-injected brains, and 3-repeat tau only in Pick disease-injected brains, all of which contained isoforms related to those found in the injected seeds. The injected abnormal tau was seeded, and accumulated at the site of injection and at neural connections, predominantly within the same site. The abnormal tau newly accumulated was found to be endogenous in these mice and to have crossed the species barrier. Of particular importance, Pick's body-like inclusions were observed in Pick's disease-injected mice, and accumulations characteristic of Pick's disease were reproduced, suggesting that we have developed the first model that recapitulates the pathology of Pick's disease. These models are not only useful for elucidating the mechanism of propagation of tau pathology involving both 3- and 4-repeat-isoforms, but can also reproduce the pathology of tauopathies, which should lead to the discovery of new therapeutic agents.
出版者・発行元
出版者・発行元(英)
誌名
誌名(英)
Brain : a journal of neurology
開始ページ
終了ページ
出版年月
2021年9月13日
査読の有無
招待の有無
掲載種別
研究論文(学術雑誌)
ISSN
DOI URL
https://doi.org/10.1093/brain/awab289
共同研究・競争的資金等の研究課題
研究者
細川 雅人 (ホソカワ マサト) , 鈴木 元治郎 , 鈴掛 雅美 (スズカケ マサミ) , Hasegawa Masato