Epigenetic changes in Alzheimer's disease: Decrements in DNA methylation

L.J. Roberts Center for Alzheimer's Research, Sun Health Research Institute, P.O. Box 1278, Sun City, AZ 85372, USA.
Neurobiology of aging (Impact Factor: 4.85). 11/2009; 31(12):2025-37. DOI: 10.1016/j.neurobiolaging.2008.12.005
Source: PubMed

ABSTRACT DNA methylation is a vital component of the epigenetic machinery that orchestrates changes in multiple genes and helps regulate gene expression in all known vertebrates. We evaluated immunoreactivity for two markers of DNA methylation and eight methylation maintenance factors in entorhinal cortex layer II, a region exhibiting substantial Alzheimer's disease (AD) pathology in which expression changes have been reported for a wide variety of genes. We show, for the first time, neuronal immunoreactivity for all 10 of the epigenetic markers and factors, with highly significant decrements in AD cases. These decrements were particularly marked in PHF1/PS396 immunoreactive, neurofibrillary tangle-bearing neurons. In addition, two of the DNA methylation maintenance factors, DNMT1 and MBD2, have been reported also to interact with ribosomal RNAs and ribosome synthesis. Consistent with these findings, DNMT1 and MBD2, as well as p66α, exhibited punctate cytoplasmic immunoreactivity that co-localized with the ribosome markers RPL26 and 5.8s rRNA in ND neurons. By contrast, AD neurons generally lacked such staining, and there was a qualitative decrease in RPL26 and 5.8s rRNA immunoreactivity. Collectively, these findings suggest epigenetic dysfunction in AD-vulnerable neurons.

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Available from: Paul D Coleman, Jul 30, 2015
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    • "These data concur with previous reports of an ADassociated reduction in 5-hmC in the hippocampus (Chouliaras et al., 2013). Although there was a regional difference in 5-fC levels, no AD-associated changes in 5-mC, 5-fC, or 5-caC were observed, although previous reports have shown decrements in 5-mC in AD EC and hippocampus (Chouliaras et al., 2013; Mastroeni et al., 2010). Given the relatively small numbers of samples assessed in this study, further research investigating the specificity of the differences in 5-hmC and 5-fC, we report, particularly across different neuron and glia subtypes, will be of particular interest to the field. "
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    ABSTRACT: Epigenetic processes play a key role in the central nervous system and altered levels of 5-methylcytosine have been associated with a number of neurologic phenotypes, including Alzheimer's disease (AD). Recently, 3 additional cytosine modifications have been identified (5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine), which are thought to be intermediate steps in the demethylation of 5-methylcytosine to unmodified cytosine. Little is known about the frequency of these modifications in the human brain during health or disease. In this study, we used immunofluorescence to confirm the presence of each modification in human brain and investigate their cross-tissue abundance in AD patients and elderly control samples. We identify a significant AD-associated decrease in global 5-hydroxymethylcytosine in entorhinal cortex and cerebellum, and differences in 5-formylcytosine levels between brain regions. Our study further implicates a role for epigenetic alterations in AD.
    Neurobiology of aging 02/2014; 35(8). DOI:10.1016/j.neurobiolaging.2014.02.002 · 4.85 Impact Factor
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    • "s , that is , the enzymes responsible for DNA methylation . For example , miR - 125b directly targets DNMT1 and DNMT3B , whereas computational predictions also point to DNMT3A as a potential miRNA target . This intricate network further extends to histone modifications , mainly via the involvement of MBDs , like MeCP2 ( Chouliaras et al . , 2010 ; Mastroeni et al . , 2011 ; Szulwach et al . , 2010 ) . Furthermore , as demonstrated in the case of let - 7b , miR - 9 , and miR - 137 , there is an intense crosstalk between miRNAs and histone - modifying proteins , like EZH2 and SIRT1 , all of which have been reported to be dysregulated in AD ."
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    ABSTRACT: Alzheimer's disease (AD) is a complex neurodegenerative disorder involving dysregulation of many biological pathways at multiple levels. Classical epigenetic mechanisms, including DNA methylation and histone modifications, and regulation by microRNAs (miRNAs), are among the major regulatory elements that control these pathways at the molecular level, with epigenetic modifications regulating gene expression transcriptionally and miRNAs suppressing gene expression posttranscriptionally. Epigenetic mechanisms and miRNAs have recently been shown to closely interact with each other, thereby creating reciprocal regulatory circuits, which appear to be disrupted in neuronal and glial cells affected by AD. Here, we review those miRNAs implicated in AD that are regulated by promoter DNA methylation and/or chromatin modifications and, which frequently direct the expression of constituents of the epigenetic machinery, concluding with the delineation of a complex epigenetic-miRNA regulatory network and its alterations in AD.
    Neurobiology of aging 10/2013; 35(4). DOI:10.1016/j.neurobiolaging.2013.10.082 · 4.85 Impact Factor
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    • "egions reveals that the observed differences are particularly pronounced in the CA1 neurons and glial cells and in the glial cells residing in the CA3 , whereas no differences were observed in the DG . The observed differences in 5 - mC are in agreement with previous reports of a global loss of methylation in the entorhinal cortex of AD patients ( Mastroeni et al . , 2010 ) and can further be linked to aberrant methylation patterns previously associated with AD ( Bakulski et al . , 2012 ; Siegmund et al . , 2007 ; Wang et al . , 2008 ) . Although the exact reason of the observed methylation changes is not yet clear , this might be related to AD - specific deficits in the nuclear transport of epigenetic m"
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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.
    Neurobiology of aging 04/2013; 34(9). DOI:10.1016/j.neurobiolaging.2013.02.021 · 4.85 Impact Factor
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