Differential effects of age and sex on tau pathology propagation in the htau mouse model: A neuropathological and proteomic study.

Abstract

INTRODUCTION: Aging is the main risk factor for Alzheimer's disease (AD), acting through still poorly understood mechanisms. AD is associated with the development of a tau pathology, a hallmark lesion propagating in the brain along neuroanatomically connected pathways. This study investigates changes in gene expression and patterns of tau pathology after induction of tau pathology propagation and the effects of age and sex on this propagation. METHODS: Young and old humanized htau mice were intracerebrally injected with pathological tau from human AD brain to induce tau pathology. RESULTS: Young and old htau male mice showed similar patterns of tau pathology propagation, whereas the density of tau pathology was increased in young compared to old female mice. Proteomic analysis demonstrated differential expression of proteins involved in endocytosis, autophagosome formation, and tau splicing. DISCUSSION: The increased tau pathology formation in young female mice suggests that involvement of selected biological mechanisms could occur early in women during their midlife to explain their sensitivity to the development of tau pathology. HIGHLIGHTS: Tau pathology induced by human PHF-tau is mainly composed of 3R-tau in htau mice. Splicing factors favoring 4R-tau are downregulated in mice with tau pathology. Tau pathology propagation is increased in young females compared to old females. Proteins implicated in endocytosis and autophagy are modified when tau pathology propagates. Some protein expressions are similarly modified in young females and during normal aging.