Gonadal hormones contribute to sex differences in behavior, pathology and epigenetic modifications in the 3×Tg-AD mouse model of Alzheimer’s disease

In sum, the results suggest that reduction in serum levels of female gonadal hormones impairs spatial learning capacity, whereas loss of male gonadal hormones enhances spatial learning and memory. In females, gonadectomy reduces binding of the repressive histone variant MacroH2A1 to the mouse Mapt gene and increases expression of the mouse App and Mapt genes without affecting Aβ₄₂ or pTau181 levels. Conversely, loss of male gonadal hormones increases binding of MacroH2A1 to the mouse Psen1 gene and decreases App expression and Aβ₄₂ levels but has no effect on tau expression. Our work suggests that adult gonadal hormones contribute to sex differences in AD-like pathology and performance in learning and memory tasks. Moreover, sex-specific differences in AD-like pathology are partially due to the action of histone variants associated with neurodegeneration, such as macroH2A1.