Epigenetics, oxidative stress, and Alzheimer disease
Zawia, NH; Lahiri, DK; Cardozo-Pelaez, F
HERO ID
539007
Reference Type
Journal Article
Subtype
Review
Year
2009
Language
English
PMID
| HERO ID | 539007 |
|---|---|
| Material Type | Review |
| In Press | No |
| Year | 2009 |
| Title | Epigenetics, oxidative stress, and Alzheimer disease |
| Authors | Zawia, NH; Lahiri, DK; Cardozo-Pelaez, F |
| Journal | Free Radical Biology and Medicine |
| Volume | 46 |
| Issue | 9 |
| Page Numbers | 1241-1249 |
| Abstract | Alzheimer disease (AD) is a progressive neurodegenerative disorder whose clinical manifestations appear in old age. The sporadic nature of 90% of AD cases, the differential susceptibility to and course of the illness, as well as the late age onset of the disease suggest that epigenetic and environmental components play a role in the etiology of late-onset AD. Animal exposure studies demonstrated that AD may begin early in life and may involve an interplay between the environment, epigenetics, and oxidative stress. Early life exposure of rodents and primates to the xenobiotic metal lead (Pb) enhanced the expression of genes associated with AD, repressed the expression of others, and increased the burden of oxidative DNA damage in the aged brain. Epigenetic mechanisms that control gene expression and promote the accumulation of oxidative DNA damage are mediated through alterations in the methylation or oxidation of CpG dinucleotides. We found that environmental influences occurring during brain development inhibit DNA-methyltransferases, thus hypomethylating promoters of genes associated with AD such as the beta-amyloid precursor protein (APP). This early life imprint was sustained and triggered later in life to increase the levels of APP and amyloid-beta (A beta). Increased A beta levels Promoted the production of reactive oxygen species, which damage DNA and accelerate neurodegenerative events. Whereas AD-associated genes were overexpressed late in life, others were repressed, suggesting that these early life perturbations result in hypomethylation as well as hypermethylation of genes. The hypermethylated genes are rendered susceptible to A beta-enhanced oxidative DNA damage because methylcytosines restrict repair of adjacent hydroxyguanosines. Although the conditions leading to early life hypo- or hypermethylation of specific genes are not known, these changes can have an impact on gene expression and imprint susceptibility to oxidative DNA damage in the aged brain. (C) 2009 Elsevier Inc. All rights reserved. |
| Doi | 10.1016/j.freeradbiomed.2009.02.006 |
| Pmid | 19245828 |
| Wosid | WOS:000265285100001 |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Language Text | English |
| Keyword | Epigenetics; DNA methylation; DNA oxidation; APP; Amyloid; Alzheimer; disease; Pb exposure; Free radicals; amyloid precursor protein; dna methylation status; adult lead-exposure; fragile-x-syndrome; promoter region; gene promoter; human brain; app; gene; transcription factors; cytosine methylation |
| Is Qa | No |
| Relationship(s) |
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