The Role of the Inactive X-Chromosome in Longevity and Neurodegeneration

Biologic sex matters in aging and neurodegeneration. A female advantage in lifespan is seen in humans and throughout the animal kingdom, and men and women suffer differing vulnerabilities to age-related neurodegenerative disorders, including Alzheimer’s disease (AD). More women suffer from AD, largely due to their longevity, as AD risk is highest in advanced age. In contrast, men with the disease die faster in populations worldwide and show greater cognitive deficits. We show the contribution of sex chromosome complement to these observations, in particular, the importance of the X chromosome. Using genetically modified mice we demonstrate (Chapter 2) that having XX sex chromosome complement increases survival during aging in male and female mice. We also show that XX sex chromosome complement in combination with ovaries extends lifespan. We go on to show (Chapter 3) that having two X chromosomes decreased mortality and conferred resilience to AD-related vulnerability in mice expressing the human amyloid precursor protein (hAPP). We then investigated how a second X chromosome can confer resilience against AD-related deficits. While XY and XX organisms express only one active X due to X chromosome inactivation (XCI), a few factors escape XCI and therefore are higher in females compared to males. One of these genes, Kdm6a, escapes in both mice and humans and is a histone demethylase linked to cognitive functions. We thus determined whether higher levels of Kdm6a – as found in the XX brain – could counter AD-related vulnerability in the XY brain. We first confirmed that the presence of a second X chromosome increased levels of Kdm6a in mouse hippocampus; it did so independent of gonadal phenotype or the presence of a Y chromosome. We then used lentiviral vectors in mice to modulate Kdm6a expression in vivo and in vitro. Overexpression of Kdm6a in the hippocampus of XY hAPP mice to higher levels observed in XX hAPP mice attenuated spatial learning and memory deficits in the Morris water maze. Similarly, overexpression of Kdm6a in XY primary neurons decreased Aβ toxicity in vitro. Furthermore, knockdown of Kdm6a in XX neurons to levels observed in XY neurons worsened Aβ toxicity in vitro. Finally, in humans, genetic variation in KDM6A was linked to higher brain expression and associated with less cognitive decline in aging and preclinical AD, suggesting relevance to human brain health. Our findings highlight the importance of sex chromosomes in aging and disease, as well as reveal a role for the baseline XCI escapee Kdm6a in countering AD-related deficits