Estrogen activates Alzheimer's disease genes

Alzheimer's and Dementia: Translational Research and Clinical Interventions - Tập 5 - Trang 906-917 - 2019
Abhirami Ratnakumar1, Samuel E. Zimmerman1, Bryen A. Jordan2,3, Jessica C. Mar1,4
1Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY, USA
2Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA
3Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA
4Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, Australia

Tóm tắt

AbstractIntroductionWomen are at increased risk for Alzheimer's disease (AD), but the reason why remains unknown. One hypothesis is that low estrogen levels at menopause increases vulnerability to AD, but this remains unproven.MethodsWe compared neuronal genes upregulated by estrogen in ovariectomized female rhesus macaques with a database of >17,000 diverse gene sets and applied a rare variant burden test to exome sequencing data from 1208 female AD patients with the age of onset < 75 years and 2162 female AD controls.ResultsWe found a striking overlap between genes upregulated by estrogen in macaques and genes downregulated in the human postmortem AD brain, and we found that estrogen upregulates the APOE gene and that progesterone acts antagonistically to estrogen genome‐wide. We also found that female patients with AD have excess rare mutations in the early menopause gene MCM8.DiscussionWe show with genomic data that the menopausal loss of estrogen could underlie the increased risk for AD in women.

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Alzheimer's and Dementia: Translational Research and Clinical Interventions

Tập 5

906-917

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