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

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.

• Authors: Takashi Saito, Naomi Mihira, Yukio Matsuba, Hiroki Sasaguri, Shoko Hashimoto, Sneha Narasimhan, Bin Zhang, Shigeo Murayama, Makoto Higuchi, Virginia M Y Lee, John Q Trojanowski, Takaomi C Saido
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 294 Issue 34 Pg. 12754-12765 (08 23 2019) ISSN: 1083-351X [Electronic] United States
• PMID: 31273083 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Saito et al.

Chemical References

• MAPT protein, human
• Mapt protein, mouse
• tau Proteins

Topics

• Animals
• Disease Models, Animal
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• tau Proteins (genetics, metabolism)