title: Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease patients.
abstract: 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 (r(p) = -0.539, p = 0.021 for 5-mC and r(p) = -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.
authors.affiliation: School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, European Graduate School of Neuroscience (EURON), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Leonidas
authors.initials: L
authors.lastname: Chouliaras
authors.forename: Diego
authors.initials: D
authors.lastname: Mastroeni
authors.forename: Elaine
authors.initials: E
authors.lastname: Delvaux
authors.forename: Andrew
authors.initials: A
authors.lastname: Grover
authors.forename: Gunter
authors.initials: G
authors.lastname: Kenis
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Hof
authors.forename: Harry W M
authors.initials: HW
authors.lastname: Steinbusch
authors.forename: Paul D
authors.initials: PD
authors.lastname: Coleman
authors.forename: Bart P F
authors.initials: BP
authors.lastname: Rutten
authors.forename: Daniel L A
authors.initials: DL
authors.lastname: van den Hove
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D003562:Cytidine / Q000031:analogs & derivatives / Q000378:metabolism; D019175:DNA Methylation; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006900:Hydroxylation; D008297:Male
chemical_list: C540838:5-hydroxymethyl-2'-deoxycytidine; D003841:Deoxycytidine; D003562:Cytidine; C016568:5-methylcytidine