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Glia-specific APOE epigenetic changes in the Alzheimer's disease brain.
- Source :
-
Brain research [Brain Res] 2018 Nov 01; Vol. 1698, pp. 179-186. Date of Electronic Publication: 2018 Aug 03. - Publication Year :
- 2018
-
Abstract
- The apolipoprotein E gene (APOE) is the strongest genetic risk factor for developing Alzheimer's disease (AD). Our recent identification of altered APOE DNA methylation in AD postmortem brain (PMB) prompted this follow-up study. Our goals were to (i) validate the AD-differential methylation of APOE in an independent PMB study cohort and (ii) determine the cellular populations (i.e., neuronal vs. non-neuronal) of AD PMB that contribute to this differential methylation. Here, we obtained an independent cohort of 57 PMB (42 AD and 15 controls) and quantified their APOE methylation levels from frontal lobe and cerebellar tissue. We also applied fluorescence-activated nuclei sorting (FANS) to separate neuronal nuclei from non-neuronal nuclei within the tissue of 15 AD and 14 control subjects. Bisulfite pyrosequencing was used to generate DNA methylation profiles of APOE from both bulk PMB and FANS nuclei. Our results provide independent validation that the APOE CGI holds lower DNA methylation levels in AD compared to control in frontal lobe but not cerebellar tissue. Our data also indicate that the non-neuronal cells of the AD brain, which are mainly composed of glia, are the main contributors to the lower APOE DNA methylation observed in AD PMB. Given that astrocytes are the primary producers of ApoE in the brain our results suggest that alteration of epigenetically regulated APOE expression in glia could be an important part of APOE's strong effect on AD risk.<br /> (Copyright © 2018. Published by Elsevier B.V.)
- Subjects :
- Aged
Aged, 80 and over
Alzheimer Disease pathology
Astrocytes pathology
Brain metabolism
CpG Islands
DNA Methylation
Epigenesis, Genetic
Female
Genetic Predisposition to Disease
Humans
Male
Neuroglia metabolism
Neurons pathology
Promoter Regions, Genetic
Alzheimer Disease genetics
Apolipoproteins E genetics
Brain physiopathology
Neuroglia pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1872-6240
- Volume :
- 1698
- Database :
- MEDLINE
- Journal :
- Brain research
- Publication Type :
- Academic Journal
- Accession number :
- 30081037
- Full Text :
- https://doi.org/10.1016/j.brainres.2018.08.006