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Glia-specific APOE epigenetic changes in the Alzheimer’s disease brain
- Source :
- Brain Research. 1698:179-186
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 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.
- Subjects :
- Male
0301 basic medicine
Apolipoprotein E
medicine.medical_specialty
Disease
Biology
Article
Epigenesis, Genetic
03 medical and health sciences
Apolipoproteins E
0302 clinical medicine
Alzheimer Disease
Internal medicine
medicine
Humans
Genetic Predisposition to Disease
Epigenetics
Promoter Regions, Genetic
Molecular Biology
Aged
Aged, 80 and over
Neurons
Postmortem brain
General Neuroscience
Brain
Methylation
DNA Methylation
Control subjects
030104 developmental biology
Endocrinology
Frontal lobe
Astrocytes
DNA methylation
CpG Islands
Female
lipids (amino acids, peptides, and proteins)
Neurology (clinical)
Neuroglia
030217 neurology & neurosurgery
Developmental Biology
Subjects
Details
- ISSN :
- 00068993
- Volume :
- 1698
- Database :
- OpenAIRE
- Journal :
- Brain Research
- Accession number :
- edsair.doi.dedup.....6eff6c03f67fec222b6e43bbea63de23