Stroke sensitivity in the aged: sex chromosome complement vs. gonadal hormones

Stroke is a sexually dimorphic disease. Elderly women not only have higher stroke incidence than age-matched men, but also have poorer recovery and higher morbidity and mortality after stroke. In older, post-menopausal women, gonadal hormone levels are similar to that of men. This suggests that tissue damage and functional outcomes are influenced by biologic sex (XX vs. XY) rather than the hormonal milieu at older ages. We employed the Four Core Genotype (FCG) mouse model to study the contribution of sex chromosome complement and gonadal hormones to stroke sensitivity in aged mice in which the testis determining gene (Sry) is removed from the Y chromosome, allowing for the generation of XX males and XY females. XXF, XXM, XYF, XYM and XYwt aged mice were subjected to middle cerebral artery occlusion (MCAO). XXF and XXM mice had significantly larger infarct volumes than XYF and XYM cohorts respectively. There was no significant difference in hormone levels among aged FCG mice. XXF/XXM mice also had more robust microglial activation and higher serum levels of pro-inflammatory cytokines than XYF/XYM cohort respectively. We concluded that the sex chromosome complement contributes to ischemic sensitivity in aged animals and leads to sex differences in innate immune responses.