Sex-specific effects of acetylation on tauopathy in aging htau mice.

Alzheimer’s disease involves extracellular β-amyloid accumulation and intracellular phosphorylated tau aggregates, with higher disease prevalence and neuropathological burden in aging females. While tau phosphorylation contributes to tau pathology, other modifications, such as acetylation, also promote aggregation. Aging disrupts proteostasis, in part through acetylation, a post-translational modification affecting protein function and stability; however, its role in sex-specific tauopathy remains unclear. This study investigated acetylation in an age-, sex-specific manner across presymptomatic (3–5 months), progressive (11–14 months), and advanced (> 16 months) stages of tauopathy in htau mice using immunoassays. In females, cortical tau K174 acetylation increased with age and disease progression, correlating with tau accumulation. In males, tau phosphorylation increased without acetylation changes, indicating sex-specific regulation. Free ubiquitin, a marker of impaired proteasomal degradation, rose with age in both females and males. Autophagy markers also showed marked age-related decline in both sexes, contributing to tau accumulation. Increased mTOR expression in aged mice further suggested mTOR-driven autophagy inhibition. These findings suggest that aging-related disruptions in brain acetylation are associated with accelerated tau pathology, with females potentially being more vulnerable due to elevated tau acetylation coinciding with impaired protein degradation pathways. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-41691-0.