期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 294, 期 34, 页码 12754-12765出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.009487
关键词
Alzheimer disease; amyloid precursor protein (APP); amyloid-beta (AB); tau protein (tau); tauopathy; dystrophic neurite; humanized mouse model; knock-in; neurodegeneration; tau propagation; dystrophic neurite; plaque deposit
资金
- RIKEN Center for Brain Science
- RIKEN Aging Project
- MEXT
- Precursory Research for Embryonic Science and Technology from JST
- Cell Science Research Foundation
- Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from the Japan Agency for Medical Research and Development (AMED) [JP18dm027001]
- Astellas Pharma, Inc. JSPS KAKENHI [JP16H06277]
- National Institutes of Health [AG10124, AG17586]
In cortical regions of brains from individuals with preclinical or clinical Alzheimer's disease (AD), extracellular beta-amyloid (A beta) 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 A beta-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 A beta-amyloidosis. In the presence of A beta-amyloidosis, tau accumulation was intensified and closely associated with dystrophic neurites, consistently showing that A beta-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.
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