@article{oai:repo.qst.go.jp:00077567,
 author = {Saito, Takashi and Mihira, Naomi and Matsuba, Yukio and Sasaguri, Hiroki and Hashimoto, Shoko and Narasimhan, Sneha and Zhang, Bin and Murayama, Shigeo and Higuchi, Makoto and M. Y. Lee, Virginia and Q. Trojanowski, John and C. Saido, Takaomi and Makoto, Higuchi},
 issue = {34},
 journal = {The Journal of Biological Chemistry},
 month = {Jul},
 note = {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.},
 pages = {12754--12765},
 title = {Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation},
 volume = {294},
 year = {2019}
}