Amyloid-beta (A beta) 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 A beta, 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 A beta does in fact cause DNA methylation/demethylation. Neprilysin (NEP) is one of the enzymes responsible for A beta degradation, with its expression decreasing in both Alzheimer and aging brains. Using high-performance liquid chromatography (HPLC), we explore whether A beta 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 A beta reduces global DNA methylation whilst increasing NEP DNA methylation and further suppressing the NEP expression in mRNA and protein levels. Our results Support that A beta 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 A beta accumulation, and that A beta may induce global DNA hypo-methylation. (C) 2008 Elsevier Inc. All rights reserved.