Experimental modeling for tauopathies: An isogenic panel of humanized MAPT knock-in mice

Tauopathies are a group of neurodegenerative diseases characterized by the aberrant accumulation of tau protein in the brain. While numerous mouse models have been developed to study tauopathies, the majority depend on tau overexpression, which may encompass non-physiological artifacts and limit the translational relevance of findings. In this review, we highlight the development and application of an isogenic panel of MAPT knock-in (KI) mouse lines that carry single or multiple pathogenic mutations within the human MAPT gene. In these models, the endogenous murine Mapt gene was replaced with the humanized MAPT sequence, and tau is expressed under the control of the native murine Mapt promoter. This approach preserves spatiotemporal regulation of tau, providing a more physiological representation of human tauopathies. As such, these mutant MAPT KI models serve as powerful tools for elucidating the pathomechanisms of tauopathies and discovering drugs that aid tau-mediated neurodegeneration.