The epigenetic effects of amyloid-beta(1-40) on global DNA and neprilysin genes in murine cerebral endothelial cells.
Amyloid-beta (Abeta) is the core component of senile plaques, which are the pathological markers for Alzheimer's disease and cerebral amyloid angiopathy. DNA methylation/demethylation plays a crucial role in gene regulation and could also be responsible for presentation of senescence. Oxidative stress, which may be induced by Abeta, is thought to be an important contributor of DNA hyper-methylation; however, contradicting this is the fact that global DNA hypo-methylation has been found in aging brains. It therefore remains largely unknown as to whether Abeta does in fact cause DNA methylation/demethylation. Neprilysin (NEP) is one of the enzymes responsible for Abeta degradation, with its expression decreasing in both Alzheimer and aging brains. Using high-performance liquid chromatography (HPLC), we explore whether Abeta is responsible for alteration of the global DNA methylation status on a murine cerebral endothelial cells model, and also use methylation-specific PCR (MSPCR) to examine whether DNA methylation status is altered on the NEP promoter region. We find that Abeta reduces global DNA methylation whilst increasing NEP DNA methylation and further suppressing the NEP expression in mRNA and protein levels. Our results support that Abeta induces epigenetic effects, implying that DNA methylation may be part of a vicious cycle involving the reduction in NEP expression along with a resultant increase in Abeta accumulation, and that Abeta may induce global DNA hypo-methylation.
Chen
Kun-Lin
KL
Department of Neurology and The Topnotch Stroke Research Center, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan.
Wang
Steven Sheng-Shih
SS
Yang
Yi-Yuan
YY
Yuan
Rey-Yue
RY
Chen
Ruei-Ming
RM
Hu
Chaur-Jong
CJ
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000201:enzymology*; D004247:DNA / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D042783:Endothelial Cells / Q000201:enzymology; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D015260:Neprilysin / Q000235:genetics*; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40); D004247:DNA; D015260:Neprilysin