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Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation
https://repo.qst.go.jp/records/77567
https://repo.qst.go.jp/records/775674fc98d03-9890-4096-a530-bf60c6181b0c
Item type | 学術雑誌論文 / Journal Article(1) | |||||
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公開日 | 2019-11-21 | |||||
タイトル | ||||||
タイトル | Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation | |||||
言語 | ||||||
言語 | eng | |||||
資源タイプ | ||||||
資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
資源タイプ | journal article | |||||
アクセス権 | ||||||
アクセス権 | metadata only access | |||||
アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
著者 |
Saito, Takashi
× Saito, Takashi× Mihira, Naomi× Matsuba, Yukio× Sasaguri, Hiroki× Hashimoto, Shoko× Narasimhan, Sneha× Zhang, Bin× Murayama, Shigeo× Higuchi, Makoto× M. Y. Lee, Virginia× Q. Trojanowski, John× C. Saido, Takaomi× Makoto, Higuchi |
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抄録 | ||||||
内容記述タイプ | Abstract | |||||
内容記述 | In cortical regions of brains from individuals with preclinical or clinical Alzheimer's disease (AD), extracellular β-amyloid (Aβ) deposition precedes the aggregation of pathological intracellular tau (the product of the gene microtubule-associated protein tau (MAPT)). To our knowledge, current mouse models of tauopathy reconstitute tau pathology by overexpressing mutant human tau protein. Here, through a homologous recombination approach that replaced the entire murine Mapt gene with the human ortholog, we developed knock-in mice with humanized Mapt to create an in vivo platform for studying human tauopathy. Of note, the humanized Mapt expressed all six tau isoforms present in humans. We next cross-bred the MAPT knock-in mice with single amyloid precursor protein (App) knock-in mice to investigate the Aβ–tau axis in AD etiology. The double-knock-in mice exhibited higher tau phosphorylation than did single MAPT knock-in mice but initially lacked apparent tauopathy and neurodegeneration, as observed in the single App knock-in mice. We further observed that tau humanization significantly accelerates cell-to-cell propagation of AD brain-derived pathological tau both in the absence and presence of Aβ-amyloidosis. In the presence of Aβ-amyloidosis, tau accumulation was intensified and closely associated with dystrophic neurites, consistently showing that Aβ-amyloidosis affects tau pathology. Our results also indicated that the pathological human tau interacts better with human tau than with murine tau, suggesting species-specific differences between these orthologous pathogenic proteins. We propose that the MAPT knock-in mice will make it feasible to investigate the behaviors and characteristics of human tau in an animal model. | |||||
書誌情報 |
The Journal of Biological Chemistry 巻 294, 号 34, p. 12754-12765, 発行日 2019-07 |
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ISSN | ||||||
収録物識別子タイプ | ISSN | |||||
収録物識別子 | 0021-9258 | |||||
PubMed番号 | ||||||
識別子タイプ | PMID | |||||
関連識別子 | 31273083 | |||||
DOI | ||||||
識別子タイプ | DOI | |||||
関連識別子 | 10.1074/jbc.RA119.009487 | |||||
関連サイト | ||||||
識別子タイプ | URI | |||||
関連識別子 | http://www.jbc.org/content/294/34/12754.long |