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J Biol Chem. 2019 Aug 23;294(34):12754-12765. doi: 10.1074/jbc.RA119.009487. Epub 2019 Jul 4.

Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation.

Author information

1
Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan takashi.saito.aa@riken.jp.
2
Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 464-8601, Japan.
3
Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan.
4
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
5
Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakaecho, Itabashi, Tokyo 173-0015, Japan.
6
Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
7
Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan saido@brain.riken.jp.

Abstract

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.

KEYWORDS:

Alzheimer disease; amyloid precursor protein (APP); amyloid-beta (AB); dystrophic neurite; humanized mouse model; knock-in; neurodegeneration; plaque deposit; tau propagation; tau protein (tau); tauopathy

PMID:
31273083
PMCID:
PMC6709628
[Available on 2020-08-23]
DOI:
10.1074/jbc.RA119.009487

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