Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease patients

Leonidas Chouliaras, Diego Mastroeni, Elaine Delvaux, Andrew Grover, Gunter Kenis, Patrick R. Hof, Harry W.M. Steinbusch, Paul Coleman, Bart P.F. Rutten, Daniel L.A. van den Hove

Research output: Contribution to journalArticle

212 Citations (Scopus)

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 (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.

Original languageEnglish (US)
Pages (from-to)2091-2099
Number of pages9
JournalNeurobiology of Aging
Volume34
Issue number9
DOIs
StatePublished - Sep 1 2013
Externally publishedYes

Fingerprint

DNA Methylation
Hippocampus
Alzheimer Disease
Epigenomics
Amyloid Plaques
Gene Expression
Neurofibrillary Tangles
Genetic Loci
Monozygotic Twins
Brain
5-methylcytidine
Pathology
DNA

Keywords

  • Alzheimer's disease
  • Amyloid
  • DNA hydroxymethylation
  • DNA methylation
  • Epigenetics

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology
  • Clinical Neurology

Cite this

Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease patients. / Chouliaras, Leonidas; Mastroeni, Diego; Delvaux, Elaine; Grover, Andrew; Kenis, Gunter; Hof, Patrick R.; Steinbusch, Harry W.M.; Coleman, Paul; Rutten, Bart P.F.; van den Hove, Daniel L.A.

In: Neurobiology of Aging, Vol. 34, No. 9, 01.09.2013, p. 2091-2099.

Research output: Contribution to journalArticle

Chouliaras, L, Mastroeni, D, Delvaux, E, Grover, A, Kenis, G, Hof, PR, Steinbusch, HWM, Coleman, P, Rutten, BPF & van den Hove, DLA 2013, 'Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease patients', Neurobiology of Aging, vol. 34, no. 9, pp. 2091-2099. https://doi.org/10.1016/j.neurobiolaging.2013.02.021
Chouliaras, Leonidas ; Mastroeni, Diego ; Delvaux, Elaine ; Grover, Andrew ; Kenis, Gunter ; Hof, Patrick R. ; Steinbusch, Harry W.M. ; Coleman, Paul ; Rutten, Bart P.F. ; van den Hove, Daniel L.A. / Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease patients. In: Neurobiology of Aging. 2013 ; Vol. 34, No. 9. pp. 2091-2099.
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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 (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.",
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AU - Hof, Patrick R.

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