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

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 ()). 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 gene with the human ortholog, we developed knock-in mice with humanized to create an platform for studying human tauopathy. Of note, the humanized expressed all six tau isoforms present in humans. We next cross-bred the knock-in mice with single amyloid precursor protein () knock-in mice to investigate the Aβ-tau axis in AD etiology. The double-knock-in mice exhibited higher tau phosphorylation than did single knock-in mice but initially lacked apparent tauopathy and neurodegeneration, as observed in the single 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 knock-in mice will make it feasible to investigate the behaviors and characteristics of human tau in an animal model.