Presenter of 1 Presentation
HUMAN MAPT KNOCK-IN MICE THAT HARBOR FAMILIAL TAUOPATHY-CAUSING MUTATIONS
Abstract
Aims
Tauopathy is characterized by accumulation of pathological tau in brain. In order to clarify the disease mechanisms, we aimed to develop mouse models that reproducibly display specific tau pathology without artifacts because the current tauopathy models depend on the overexpression paradigm. The purpose of this study is to develop new tauopathy mouse models by knock-in strategy.
Methods
Previously we generated human MAPT knock-in (hTau-KI) mice, in which the entire Mapt gene was humanized. The hTau-KI mice express all six isoforms (Hashimoto et al.,2019; Saito et al., 2019). In this study, several tauopathy-causing mutations were introduced into hTau-KI mice by Base Editor, a new CRISPR/Cas9-based genome editing technology.
Results
We obtained several tauopathy mouse models (hTau-KI P301L, hTau-KI P301S, hTau-KI P301V, hTau-KI Intron10+3 G>A, hTau-KI P301L; Intron10+3 G>A, hTau-KI P301S; Intron10+3 G>A). Immunohistochemical analyses showed phospho-tau positive signals in the entorhinal cortex and other areas in some of these lines. In addition, biochemical analyses demonstrated that the intronic mutation altered the expression patterns of 3 and 4 repeat tau. Finally, we crossbred these mutant hTau-KI mice with App knock-in mice and found that amyloid pathology accelerated the tau pathology in the brain.
Conclusions
We successfully introduced tauopathy-causing mutations in hTau-KI mice. Consequently, we identified the effects of these MAPT mutations on the pathological and cognitive parameters. We expect these models to contribute to the research community for better understanding the mechanisms of tauopathies.