Oxidative stress induces DNA demethylation and histone acetylation in SH-SY5Y cells: potential epigenetic mechanisms in gene transcription in Aβ production.

Overwhelming evidence has suggested that enhanced oxidative stress is involved in the pathogenesis and/or progression of Alzheimer's disease (AD). Amyloid-β (Aβ) that composes senile plaques plays a causal role in AD, and its abnormal deposition in brains is the typical neuropathologic hallmark of AD. Recent studies have suggested that epigenetic mechanisms play an important role in the initiation and development of AD. In the present study, we investigated the epigenetic mechanisms, such as DNA methylation and histone acetylation, involved in the transcription of AD-related genes with Aβ production under oxidative stress. Human neuroblastoma SH-SY5Y cells were treated with hydrogen peroxide (H(2)O(2)) and used as the cell model. The intracellular Aβ level was significantly increased in H(2)O(2)-treated SH-SY5Y cells. The expression of amyloid-β precursor protein and β-site amyloid-β precursor protein-cleaving enzyme 1 was upregulated by demethylation in the gene promoters associated with the reduction of methyltransferases. Meanwhile, H(2)O(2) induced the upregulation of histone acetyltransferases p300/cAMP-response element binding protein (p300/CBP) and downregulation of histone deacetylases. DNA hypomethylation induced by DNA methyltransferase inhibitor could activate the DNA binding activity of transcription factor nuclear factor-κB, whereas no significant effect was observed on specific protein 1. DNA binding activities of nuclear factor-κB and specific protein 1 were activated by histone hyperacetylation induced by histone deacetylase inhibitor. These findings suggested that oxidative stress resulted in an imbalance between DNA methylation and demethylation and histone acetylation and deacetylation associated with the activation of transcription factors, leading to the AD-related gene transcription in the Aβ overproduction. This could be a potential mechanism for oxidative stress response, which might contribute to the pathogenesis and development of AD.