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: 5.01). 11/2009; 31(12):2025-37. DOI: 10.1016/j.neurobiolaging.2008.12.005
Source: PubMed


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.


Available from: Paul D Coleman
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    • "The authors suggested that longer lifespan increases the risk of environment-induced epigenetic changes. In a detailed study [25] of epigenetics in AD, decreased DNA methylation was observed in the temporal neocortex of monozygotic AD twins. Manipulation of histone tail acetylation with HDAC inhibitors also has been investigated in several animal models of AD [26]. "
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    • "The complex etiology of LOAD suggests that the pathology results from intricate interplay of genetic predisposition and environmental factors. This interplay is reflected in epigenomic and transcriptomic alteration of neural cells during disease progression [56] [57] [58]. Transcriptome profiling is an important tool in studying complex disorders to identify end-stage alterations that converge from interaction of multiple genetic, epigenetic, and environmental factors. "
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    • "The methylation reaction is catalysed by DNA methyltransferase enzymes in the presence of the methyl donor S-adenosyl methionine, and it usually brings about the repression of gene expression. In AD patients, significant alterations in genome-wide DNA methylation patterns were described; moreover, different methylation levels of specific genes were observed in comparison to controls, although sometimes the direction of regulation was inconsistent between studies [15] [16] [17] [18] [19] [20] [21]. Nevertheless, contrasting results of no correlation with methylation levels were also reported [22] [23] and these discrepancies suggest that the issue deserves further investigation. "
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