X, but Not Y, Chromosomal Complement Contributes to Stroke Sensitivity in Aged Animals

Post-menopausal women become vulnerable to stroke and have poorer outcomes and higher mortality than age-matched men, and previous studies suggested that sex chromosomes play a vital role in mediating stroke sensitivity in the aged. It is unknown if this is due to effects of the X or Y chromosome. The present study used the XY* mouse model (with four genotypes: XX and XO gonadal females and XY and XXY gonadal males) to compare the effect of the X vs. Y chromosome compliment in stroke. Aged (18-20 months) and gonadectomized young (8-12 weeks) mice were subjected to a 60-min middle cerebral artery occlusion. Infarct volume and behavioral deficits were quantified 3 days after stroke. Microglial activation and infiltration of peripheral leukocytes in the aged ischemic brain were assessed by flow cytometry. Plasma inflammatory cytokine levels by ELISA, and brain expression of two X chromosome-linked genes, KDM6A and KDM5C by immunochemistry, were also examined. Both aged and young XX and XXY mice had worse stroke outcomes compared to XO and XY mice, respectively; however, the difference between XX vs. XXY and XO vs. XY aged mice was minimal. Mice with two copies of the X chromosome showed more robust microglial activation, higher brain-infiltrating leukocytes, elevated plasma cytokine levels, and enhanced co-localization of KDM6A and KDM5C with Iba1 cells after stroke than mice with one X chromosome. The number of X chromosomes mediates stroke sensitivity in aged mice, which might be processed through the X chromosome-linked genes and the inflammatory responses.