| First Author | Saito T | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 34 | Pages | 12754-12765 |
| PubMed ID | 31273083 | Mgi Jnum | J:280392 |
| Mgi Id | MGI:6369293 | Doi | 10.1074/jbc.RA119.009487 |
| Citation | Saito T, et al. (2019) Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation. J Biol Chem 294(34):12754-12765 |
| abstractText | In cortical regions of brains from individuals with preclinical or clinical Alzheimer's disease (AD), extracellular beta-amyloid (Abeta) 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 Abeta-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 Abeta-amyloidosis. In the presence of Abeta-amyloidosis, tau accumulation was intensified and closely associated with dystrophic neurites, consistently showing that Abeta-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. |
