Open AccessA second X chromosome contributes to resilience in a mouse model of Alzheimer’s disease
Author(s) -
Emily Jane Davis,
Lauren Broestl,
Samira Abdulai-Saiku,
Kurtresha Worden,
Luke W. Bonham,
Elena Miñones-Moyano,
Arturo J. Moreno,
Dan Wang,
Kevin Chang,
Gina Williams,
Bayardo I. Garay,
Iryna Lobach,
Nino Devidze,
Daniel Kim,
Cliff Anderson-Bergman,
Gui-Qiu Yu,
Charles C. White,
Julie A. Harris,
Bruce L. Miller,
David A. Bennett,
Arthur P. Arnold,
Phil L. de Jager,
Jorge J. Palop,
Barbara Panning,
Jennifer S. Yokoyama,
Lennart Mucke,
Dena Dubal
Publication year - 2020
Publication title -
science translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.819
H-Index - 216
eISSN - 1946-6242
pISSN - 1946-6234
DOI - 10.1126/scitranslmed.aaz5677
Subject(s) - disease , resilience (materials science) , alzheimer's disease , chromosome , biology , neuroscience , genetics , medicine , gene , pathology , physics , thermodynamics
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.