Research ArticleAlzheimer’s Disease

A second X chromosome contributes to resilience in a mouse model of Alzheimer’s disease

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Science Translational Medicine  26 Aug 2020:
Vol. 12, Issue 558, eaaz5677
DOI: 10.1126/scitranslmed.aaz5677

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The advantage of an extra X

Whether sex chromosomes contribute to sex difference in Alzheimer’s disease (AD) is unknown. In AD, men die earlier, whereas women live longer. During aging and preclinical AD, men show more cognitive deficits than do women. Davis et al. now report that the X chromosome may affect AD-related vulnerability in a mouse model of AD. Engineering mice to harbor a second X chromosome conferred resilience in male and female mice, in part through Kdm6a, an X chromosome gene that escapes inactivation. In humans, variation in the KDM6A gene was associated with higher expression in the brain and less cognitive decline. These results imply that having a second X chromosome could contribute to counteracting AD vulnerability.

Abstract

A major sex difference in Alzheimer’s disease (AD) is that men with the disease die earlier than do women. In aging and preclinical AD, men also show more cognitive deficits. Here, we show that the X chromosome affects AD-related vulnerability in mice expressing the human amyloid precursor protein (hAPP), a model of AD. XY-hAPP mice genetically modified to develop testicles or ovaries showed worse mortality and deficits than did XX-hAPP mice with either gonad, indicating a sex chromosome effect. To dissect whether the absence of a second X chromosome or the presence of a Y chromosome conferred a disadvantage on male mice, we varied sex chromosome dosage. With or without a Y chromosome, hAPP mice with one X chromosome showed worse mortality and deficits than did those with two X chromosomes. Thus, adding a second X chromosome conferred resilience to XY males and XO females. In addition, the Y chromosome, its sex-determining region Y gene (Sry), or testicular development modified mortality in hAPP mice with one X chromosome such that XY males with testicles survived longer than did XY or XO females with ovaries. Furthermore, a second X chromosome conferred resilience potentially through the candidate gene Kdm6a, which does not undergo X-linked inactivation. In humans, genetic variation in KDM6A was linked to higher brain expression and associated with less cognitive decline in aging and preclinical AD, suggesting its relevance to human brain health. Our study suggests a potential role for sex chromosomes in modulating disease vulnerability related to AD.

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