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 (
The mammalian sex chromosome system (XX female/XY male) is ancient and highly conserved. The sex chromosome karyotype of the creeping vole (
- NSF-PAR ID:
- 10226707
- Publisher / Repository:
- American Association for the Advancement of Science (AAAS)
- Date Published:
- Journal Name:
- Science
- Volume:
- 372
- Issue:
- 6542
- ISSN:
- 0036-8075
- Page Range / eLocation ID:
- p. 592-600
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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