TY - JOUR
T1 - Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease patients
AU - Chouliaras, Leonidas
AU - Mastroeni, Diego
AU - Delvaux, Elaine
AU - Grover, Andrew
AU - Kenis, Gunter
AU - Hof, Patrick R.
AU - Steinbusch, Harry W.M.
AU - Coleman, Paul D.
AU - Rutten, Bart P.F.
AU - van den Hove, Daniel L.A.
N1 - Funding Information:
Funds have been provided by the Internationale Stichting Alzheimer Onderzoek (ISAO) , grant number 07551 and 11532 (D.L.A. vdH.), by the ISAO grant number 09552 , and the Netherlands Organization for Scientific Research (NWO, Veni Award 916.11.086) (B.P.F.R.), and by a Marie Curie Host Fellowship Grant MC-EST 020589 EURON (L.C). P.R.H. is supported by National Institutes of Health ( NIH ) grant P50 AG05138 . P.D.C. is supported by NIH RO1 AG036400 grant and Arizona Alzheimer's Research Center DHS Award FY 2012.
PY - 2013/9
Y1 - 2013/9
N2 - Epigenetic dysregulation of gene expression is thought to be critically involved in the pathophysiology of Alzheimer's disease (AD). Recent studies indicate that DNA methylation and DNA hydroxymethylation are 2 important epigenetic mechanisms that regulate gene expression in the aging brain. However, very little is known about the levels of markers of DNA methylation and hydroxymethylation in the brains of patients with AD, the cell-type specificity of putative AD-related alterations in these markers, as well as the link between epigenetic alterations and the gross pathology of AD. The present quantitative immunohistochemical study investigated the levels of the 2 most important markers of DNA methylation and hydroxymethylation, that is, 5-methylcytidine (5-mC) and 5-hydroxymethylcytidine (5-hmC), in the hippocampus of AD patients (n = 10) and compared these to non-demented, age-matched controls (n = 10). In addition, the levels of 5-hmC in the hippocampus of a pair of monozygotic twins discordant for AD were assessed. The levels of 5-mC and 5-hmC were furthermore analyzed in a cell-type and hippocampal subregion-specific manner, and were correlated with amyloid plaque load and neurofibrillary tangle load. The results showed robust decreases in the hippocampal levels of 5-mC and 5-hmC in AD patients (19.6% and 20.2%, respectively). Similar results were obtained for the twin with AD when compared to the non-demented co-twin. Moreover, levels of 5-mC as well as the levels of 5-hmC showed a significant negative correlation with amyloid plaque load in the hippocampus (rp = -0.539, p = 0.021 for 5-mC and rp = -0.558, p = 0.016 for 5-hmC). These human postmortem results thus strengthen the notion that AD is associated with alterations in DNA methylation and hydroxymethylation, and provide a basis for further epigenetic studies identifying the exact genetic loci with aberrant epigenetic signatures.
AB - Epigenetic dysregulation of gene expression is thought to be critically involved in the pathophysiology of Alzheimer's disease (AD). Recent studies indicate that DNA methylation and DNA hydroxymethylation are 2 important epigenetic mechanisms that regulate gene expression in the aging brain. However, very little is known about the levels of markers of DNA methylation and hydroxymethylation in the brains of patients with AD, the cell-type specificity of putative AD-related alterations in these markers, as well as the link between epigenetic alterations and the gross pathology of AD. The present quantitative immunohistochemical study investigated the levels of the 2 most important markers of DNA methylation and hydroxymethylation, that is, 5-methylcytidine (5-mC) and 5-hydroxymethylcytidine (5-hmC), in the hippocampus of AD patients (n = 10) and compared these to non-demented, age-matched controls (n = 10). In addition, the levels of 5-hmC in the hippocampus of a pair of monozygotic twins discordant for AD were assessed. The levels of 5-mC and 5-hmC were furthermore analyzed in a cell-type and hippocampal subregion-specific manner, and were correlated with amyloid plaque load and neurofibrillary tangle load. The results showed robust decreases in the hippocampal levels of 5-mC and 5-hmC in AD patients (19.6% and 20.2%, respectively). Similar results were obtained for the twin with AD when compared to the non-demented co-twin. Moreover, levels of 5-mC as well as the levels of 5-hmC showed a significant negative correlation with amyloid plaque load in the hippocampus (rp = -0.539, p = 0.021 for 5-mC and rp = -0.558, p = 0.016 for 5-hmC). These human postmortem results thus strengthen the notion that AD is associated with alterations in DNA methylation and hydroxymethylation, and provide a basis for further epigenetic studies identifying the exact genetic loci with aberrant epigenetic signatures.
KW - Alzheimer's disease
KW - Amyloid
KW - DNA hydroxymethylation
KW - DNA methylation
KW - Epigenetics
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U2 - 10.1016/j.neurobiolaging.2013.02.021
DO - 10.1016/j.neurobiolaging.2013.02.021
M3 - Article
C2 - 23582657
AN - SCOPUS:84878944565
SN - 0197-4580
VL - 34
SP - 2091
EP - 2099
JO - Neurobiology of Aging
JF - Neurobiology of Aging
IS - 9
ER -