Partial reprogramming by cyclical overexpression of Yamanaka factors improves pathological phenotypes of tauopathy mouse model of human Alzheimer's disease

Abstract

Partial reprogramming induced by the controlled and cyclical overexpression of Yamanaka factors in the nervous system has so far succeeded in reversing some aging-associated phenotypes, such as improving memory function. These promising results suggest that partial reprogramming could be a potential strategy to prevent or mitigate aging-related pathologies like tauopathies, including Alzheimer’s disease. Here, we explore the potential of this strategy in addressing tauopathy development in the P301S mouse model. To achieve this, a new transgenic animal was created that can inducibly overexpress Yamanaka factors upon doxycycline administration and carries the Tau-P301S mutation, which leads to tauopathy development. The results of this study show a significant improvement in key pathological features of tauopathies in the hippocampus, including reversed tauopathy, alleviated reactive astrogliosis, age-related reduction of the H3K9me3 epigenetic marker, along with improved spatial memory, which has been described as deteriorated in this model. These findings reinforce the potential of partial reprogramming as a therapeutic strategy to combat brain pathologies associated with aging. • We engineered a transgenic mouse model expressing Yamanaka factors in a conditional manner and mutant tau protein. • This model allowed us to study tau pathology in Central Nervous system. • Tauopathy present after inducible expression of Yamanaka factors led to reduced tau phosphorylation and reduced astrogliosis. • The study also observed enhanced spatial memory and a reversal of age-related epigenetic changes. • This strategy may help prevent aging-related diseases like Alzheimer’s by reversing certain pathological features

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