DNA Methylation in Neurodegenerative and Cerebrovascular Disorders

Abstract

DNA methylation is an epigenetic mechanism by which methyl groups are added to DNA, playing a crucial role in gene expression regulation. The aim of the present study is to compare methylation status of healthy subjects with that of patients with Alzheimer’s, Parkinson’s or Cerebrovascular diseases. We also analyze methylation status of a transgenic Alzheimer’s disease mouse model (3xTg-AD). Our results show that both global methylation (n = 141) and hydroxymethylation (n = 131) levels are reduced in DNA samples from buffy coats of patients with neurodegenerative disorders and age-related cerebrovascular disease. The importance of methylation and hydroxymethylation reduction is stressed by the finding that DNMT3a mRNA levels are also downregulated in buffy coats of patients with Dementia (n = 25). Global methylation is also reduced in brain, liver and serum samples of 3xTg-AD vs. wild type mice, such as DNMT3a mRNA levels that are also decreased in the brain of 3xTg-AD (n = 10). These results suggest that the use of global methylation and hydroxymethylation levels, together with the study of DNMT3a expression, could be useful as a new diagnostic biomarker for these prevalent disorders.

Neuroprotective Effect of Piracetam against Cocaine-Induced Neuro Epigenetic Modification of DNA Methylation in Astrocytes

“…Global DNA hypomethylation has a significant impact on the progression of various neurodegenerative diseases and can induce undesirable gene activation, leading to genomic instability [ 18 , 25 ]. To evaluate global DNA methylation, cells were treated with or without cocaine (1 µM) and piracetam (10 µM) for 24 h. We used the colorimetric method to quantify global DNA methylation (5-mC).…”

“…Furthermore, DNA demethylation is regulated by the ten–eleven translocation (TET) enzymes TET1-3, which help to convert 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) [ 17 , 18 ] DNA demethylation involves the direct removal of the methyl group from 5-mC, base excision of 5-mC by DNA glycosylases, and nucleotide excision of 5-mC by endonucleases [ 19 ]. Global and site-specific changes in DNA methylation are observed in addiction [ 20 ].…”

Epigenetics: Recent Advances and Its Role in the Treatment of Alzheimer's Disease

“…Global high levels of 5-mC and a reduction of 5-hmC were observed in the 5xFAD mouse model, which are related to cognition and paralleled with Aβ deposition (86). In the 3xTg-AD mouse model, global methylation and hydroxymethylation levels are reduced (87). In the SAMP8 mouse model, global DNA methylation levels are decreased while 5-hmC levels are upregulated (88).…”

Functional Foods: An Approach to Modulate Molecular Mechanisms of Alzheimer’s Disease

“…Regarding DNMT3, a gene closely related to learning and memory functions [354,355], the authors observed a significant reduction of over 40% in DNMT3a expression in the brain of 3xTg-AD mice. Further evidence about the importance of DNMTs in the aging process is the fact that the hippocampus of aged mice shows a decrease in the expression of DNMT3a while its overexpression can reverse spatial memory deficits [354].…”

“…Based on the observation that the levels of 5mC and DNA methyltransferase decreased in AD patients, it has been suggested that global DNA hypomethylation is associated with AD [355]. Furthermore, the methylation level of essential substrates, such as the universal methyl donor SAM, the S-adenosylhomocystein (SAH) and folate, were also decreased in human AD brains [356].…”