Article

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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    • "Furthermore, some of the DNA methylation deficits in humans were recently found to be specific to brain-regions such as the temporal cortex and the cerebellum (Ladd-Acosta et al., 2013) that are associated with different forms of learning and memory. Similarly, AD is associated with epigenetic alterations in DNA methylation (Mastroeni et al., 2010) and abnormal micro-RNAs expression (Barak et al., 2013). Altered patterns of DNA methylation in immune system and nervous system development genes were found in PTSD (Uddin et al., 2010; Mehta et al., 2013), and schizophrenic patients show decreased genome-wide DNA methylation (Bonsch et al., 2012) and altered DNA demethylation mechanisms (Dong et al., 2012). "
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    • "Human postmortem case-control studies have demonstrated global hypomethylation in the entorhinal cortex of AD subjects [106] and in the temporal neocortex of an AD monozygotic twin relative to the cognitively normal twin [107]. "
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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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