Global changes in DNA methylation and hydroxymethylation in Alzheimer's disease human brain

被引:254
作者
Coppieters, Natacha [1 ,2 ,3 ,4 ]
Dieriks, Birger V. [4 ,5 ]
Lill, Claire [4 ,5 ]
Faull, Richard L. M. [4 ,5 ]
Curtis, Maurice A. [4 ,5 ]
Dragunow, Mike [1 ,2 ,3 ,4 ]
机构
[1] Univ Auckland, Dept Pharmacol, Auckland 1, New Zealand
[2] Univ Auckland, Dept Clin Pharmacol, Auckland 1, New Zealand
[3] Univ Auckland, Gravida Natl Ctr Growth & Dev, Auckland 1, New Zealand
[4] Univ Auckland, Ctr Brain Res, Auckland 1, New Zealand
[5] Univ Auckland, Dept Anat Radiol, Auckland 1, New Zealand
关键词
Alzheimer's disease; Epigenetics; DNA methylation; 5-Methylcytosine (5mC); DNA hydroxymethylation; 5-Hydroxymethylcytosine (5hmC); Human brain; PRECURSOR PROTEIN GENE; NEUROFIBRILLARY TANGLES; 5-HYDROXYMETHYLCYTOSINE; AGE; UBIQUITIN; 5-METHYLCYTOSINE; HYPOMETHYLATION; QUANTIFICATION; HIPPOCAMPUS; PROMOTER;
D O I
10.1016/j.neurobiolaging.2013.11.031
中图分类号
R592 [老年病学]; C [社会科学总论];
学科分类号
03 ; 0303 ; 100203 ;
摘要
DNA methylation (5-methylcytosine [5mC]) is one of several epigenetic markers altered in Alzheimer's disease (AD) brain. More recently, attention has been given to DNA hydroxymethylation (5-hydroxymethylcytosine [5hmC]), the oxidized form of 5mC. Whereas 5mC is generally associated with the inhibition of gene expression, 5hmC has been associated with increased gene expression and is involved in cellular processes such as differentiation, development, and aging. Recent findings point toward a role for 5hmC in the development of diseases including AD, potentially opening new pathways for treating AD through correcting methylation and hydroxymethylation alterations. In the present study, levels of 5mC and 5hmC were investigated in the human middle frontal gyrus (MFG) and middle temporal gyrus (MTG) by immunohistochemistry. Immunoreactivity for 5mC and 5hmC were significantly increased in AD MFG (N = 13) and MTG (N = 29) compared with age-matched controls (MFG, N 13 and MTG, N = 29). Global levels of 5mC and 5hmC positively correlated with each other and with markers of AD including amyloid beta, tau, and ubiquitin loads. Our results showed a global hypermethylation in the AD brain and revealed that levels of 5hmC were also significantly increased in AD MFG and MTG with no apparent influence of gender, age, postmortem delay, or tissue storage time. Using double-fluorescent immunolabeling, we found that in control and AD brains, levels of 5mC and 5hmC were low in astrocytes and microglia but were elevated in neurons. In addition, our colocalization study showed that within the same nuclei, 5mC and 5hmC mostly do not coexist. The present study clearly demonstrates the involvement of 5mC and 5hmC in AD emphasizing the need for future studies determining the exact time frame of these epigenetic changes during the progression of AD pathology. (C) 2014 Elsevier Inc. All rights reserved.
引用
收藏
页码:1334 / 1344
页数:11
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