Rats Display Sexual Dimorphism in Phosphorylation of Brain Tau with Age

BACKGROUND: Women have a two-fold higher risk than men to Alzheimer's disease (AD) at midlife. Larger brain tau burden was consistently shown in older women than age-matched men. The biological basis for this gender disparity remains elusive. OBJECTIVE: We sought to know whether tau expression and phosphorylation physiologically differ between males and females. METHODS: We used western blots and immunohistochemistry to compare the levels of total tau and phosphorylated tau in the hippocampus and entorhinal cortex (EC) between sexes in Wistar rats at 40 days, and 8 and 20 months of age. RESULTS: We detected no statistically significant difference in total tau, 3R-tau, and 4R-tau between sexes. However, female rats exhibited lower levels of tau unphosphorylated at the Tau-1 site at 40 days of age. At 8 months of age, females showed higher levels of tau phosphorylated at Ser190, Ser387, and Ser395 (Ser199, Ser396, and Ser404 of human tau, respectively) than males in EC. At 20 months of age, both brain regions of female rats consistently showed higher levels than males of tau phosphorylated at Ser253, Ser387, PHF-1 (Ser387/395), and Ser413 sites, which correspond to Ser262, Ser396, Ser396/404, and Ser422 of human tau, respectively. CONCLUSION: Rats of both sexes have comparable levels of total tau, 3R-tau, and 4R-tau, whereas females exhibit higher levels of tau phosphorylated at multiple sites that are implicated in AD tau pathology, indicating a sexual dimorphism of tau phosphorylation that may potentially underlie the disparity in brain tau burden and risk for AD between sexes.