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RSS FeedsHumanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation [Molecular Bases of Disease] (Journal of Biological Chemistry)

 
 

23 august 2019 14:03:05

 
Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation [Molecular Bases of Disease] (Journal of Biological Chemistry)
 


In cortical regions of brains from individuals with preclinical or clinical Alzheimer`s disease (AD), extracellular ?-amyloid (A?) 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?-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?-amyloidosis. In the presence of A?-amyloidosis, tau accumulation was intensified and closely associated with dystrophic neurites, consistently showing that A?-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.


 
161 viewsCategory: Biochemistry
 
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