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A second X chromosome contributes to resilience in a mouse model of Alzheimer's disease.
Davis, Emily J; Broestl, Lauren; Abdulai-Saiku, Samira; Worden, Kurtresha; Bonham, Luke W; Miñones-Moyano, Elena; Moreno, Arturo J; Wang, Dan; Chang, Kevin; Williams, Gina; Garay, Bayardo I; Lobach, Iryna; Devidze, Nino; Kim, Daniel; Anderson-Bergman, Cliff; Yu, Gui-Qiu; White, Charles C; Harris, Julie A; Miller, Bruce L; Bennett, David A; Arnold, Arthur P; De Jager, Phil L; Palop, Jorge J; Panning, Barbara; Yokoyama, Jennifer S; Mucke, Lennart; Dubal, Dena B.
Afiliación
  • Davis EJ; Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Broestl L; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Abdulai-Saiku S; Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Worden K; Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Bonham LW; Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Miñones-Moyano E; Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Moreno AJ; Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Wang D; Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Chang K; Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Williams G; Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Garay BI; Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Lobach I; Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Devidze N; Neurosciences Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Kim D; Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Anderson-Bergman C; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Yu GQ; Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
  • White CC; Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
  • Harris JA; Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
  • Miller BL; Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
  • Bennett DA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Arnold AP; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
  • De Jager PL; Allen Institute for Brain Science, Seattle, WA 98109, USA.
  • Palop JJ; Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Panning B; Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Yokoyama JS; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
  • Mucke L; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Dubal DB; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
Sci Transl Med ; 12(558)2020 08 26.
Article en En | MEDLINE | ID: mdl-32848093
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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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Enfermedad de Alzheimer Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Enfermedad de Alzheimer Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos