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

被引：121

作者：

Davis, Emily J. ^{[1
,2
,3
]}

Broestl, Lauren ^{[1
,2
,16
]}

Abdulai-Saiku, Samira ^{[1
,2
]}

Worden, Kurtresha ^{[1
,2
,17
]}

Bonham, Luke W. ^{[1
,2
,4
]}

Minones-Moyano, Elena ^{[1
,2
,18
]}

Moreno, Arturo J. ^{[1
,2
]}

Wang, Dan ^{[1
,2
]}

Chang, Kevin ^{[1
,2
]}

Williams, Gina ^{[1
,2
,5
]}

Garay, Bayardo, I ^{[1
,2
,19
]}

Lobach, Iryna ^{[6
]}

Devidze, Nino ^{[7
,20
]}

Kim, Daniel ^{[7
]}

Anderson-Bergman, Cliff ^{[8
,21
]}

Yu, Gui-Qiu ^{[7
]}

White, Charles C. ^{[9
,10
]}

Harris, Julie A. ^{[11
]}

Miller, Bruce L. ^{[1
,2
,4
]}

Bennett, David A. ^{[12
]}

Arnold, Arthur P. ^{[13
]}

De Jager, Phil L. ^{[10
]}

Palop, Jorge J. ^{[1
,2
,3
,5
,7
]}

Panning, Barbara ^{[14
]}

Yokoyama, Jennifer S. ^{[1
,2
,4
,15
]}

Mucke, Lennart ^{[1
,2
,3
,5
,7
]}

Dubal, Dena B. ^{[1
,2
,3
,5
]}

机构：

[1] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA

[2] Univ Calif San Francisco, Weill Inst Neurosci, San Francisco, CA 94158 USA

[3] Univ Calif San Francisco, Biomed Sci Grad Program, San Francisco, CA 94143 USA

[4] Univ Calif San Francisco, Memory & Aging Ctr, San Francisco, CA 94158 USA

[5] Univ Calif San Francisco, Neurosci Grad Program, San Francisco, CA 94158 USA

[6] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94158 USA

[7] Gladstone Inst Neurol Dis, San Francisco, CA 94158 USA

[8] Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA

[9] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[10] Columbia Univ, Ctr Translat & Computat Neuroimmunol, Dept Neurol, Med Ctr, New York, NY 10032 USA

[11] Allen Inst Brain Sci, Seattle, WA 98109 USA

[12] Rush Univ, Rush Alzheimers Dis Ctr, Med Ctr, Chicago, IL 60612 USA

[13] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA 90095 USA

[14] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA

[15] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA

[16] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63130 USA

[17] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA

[18] Synthego Corp, Menlo Pk, CA 94025 USA

[19] Univ Minnesota, Med Sch, Minneapolis, MN 55455 USA

[20] Sparks Therapeut Inc, Philadelphia, PA 19104 USA

[21] Lawrence Livermore Natl Lab, Livermore, CA 94550 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2020年 / 12卷 / 558期

基金：

加拿大健康研究院;

关键词：

MILD COGNITIVE IMPAIRMENT; VASCULAR RISK-FACTORS; AMYOTROPHIC-LATERAL-SCLEROSIS; SYNDROME GENES KMT2D; KABUKI SYNDROME; GENDER-DIFFERENCES; PARKINSON-DISEASE; TRANSGENIC MICE; SEX-DIFFERENCES; APOE EPSILON-4;

D O I：

10.1126/scitranslmed.aaz5677

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 (Sly), 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.

引用

页数：16

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