Alterations in global DNA methylation and hydroxymethylation are not detected in Alzheimer's disease

Abstract

AimsGenetic factors do not seem to account fully for Alzheimer disease (AD) pathogenesis. There is evidence for the contribution of environmental factors, whose effect may be mediated by epigenetic mechanisms. Epigenetics involves the regulation of gene expression independently of DNA sequence and these epigenetic changes are influenced by age and environmental factors, with DNA methylation being one of the best characterized epigenetic mechanisms. The human genome is predominantly methylated on CpG motifs, which results in gene silencing; however methylation within the body of the gene may mark active transcription. There is evidence suggesting an involvement of environmental factors in the pathogenesis of Alzheimer's disease (AD), which prompted our study examining DNA methylation in this disorder.MethodsUsing immunohistochemistry with 5‐methylcytosine/5‐hydroxymethylcytosine antibodies we studied, in comparison with age matched controls, DNA methylation in sporadic and familial AD cases in the entorhinal cortex that exhibits substantial pathology and the cerebellum, which is relatively spared.ResultsNeuronal nuclear labelling with 5‐methylcytosine (5mC) and 5‐hydroxymethylcytosine (5hmC) was evident in all cases studied. We did not detect any significant change in the levels of nuclear staining in the AD samples compared to neurologically normal controls. In the entorhinal cortex we also examined global DNA methylation and hydroxymethylation using an enzyme‐linked immunosorbent assay (ELISA).ConclusionNo significant differences were found between AD and control cases in global levels of 5mC and 5hmC in the entorhinal cortex using immunohistochemistry and enzyme‐linked immunosorbent assays.

DNA Methylation and Hydroxymethylation Levels in Relation to Two Weight Loss Strategies: Energy-Restricted Diet or Bariatric Surgery

“…In this way, 5-hmC methylation could be an epigenetic mechanism participating in disease development, although these outcomes are still under investigation [44,48]. Due to the large presence of 5-hmC in the brain [49], several studies have been conducted in neurological diseases [50,51]. However, our findings are apparently the first to demonstrate the association between obesity features and 5-hmC methylation.…”

Peripheral leukocyte expression of the potential biomarker proteins Bdnf, Sirt1, and Psen1 is not regulated by promoter methylation in Alzheimer's disease patients

“…A c c e p t e d M a n u s c r i p t 5 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.…”

“…In AD patients, gene expression control involving altered promoter methylation have been reported both at genome-wide level and in specific genes, supporting the notion that this epigenetic mechanism of regulation plays an important role in the pathophysiological processes of the disease Page 9 of 20 A c c e p t e d M a n u s c r i p t 8 [15][16][17][18][19]21]. However, the direction of increased versus reduced methylation levels shows inconsistencies between studies, both at a global level of methylation (eg.…”

Elevated Global DNA Methylation Is Not Exclusive to Amyotrophic Lateral Sclerosis and Is Also Observed in Spinocerebellar Ataxia Types 1 and 2

“…Elevation in global levels of DNA methylation has been reported in Alzhei­mer’s disease blood [65] but not in other tissue types, such as the entorhinal cortex [66], where a decrease in global hydroxymethylation was previously reported [67]. Studies in ALS have also reported increased global DNA methylation, both in the spinal cord [15] and blood samples [16] of sALS patients, but their results regarding global DNA methylation detectable in blood have been conflicting.…”