Oxidative stress and inflammation as the pathoogical components of Alzheimer s disease (AD) have been well understood.Among a diversity of mitogen-activated proein kinase (MAPK) family members, JNK and p38 MAPK subfamilies are relevant to the response of environmental stress, inflammatory stimuli, or other insults.Recent studies have demonstrated that epigenetic mechanisms may play a pivotal role in AD pathogenesis and development.In the present study, we have investigated epigenetic mechanisms such as DNA methylation and histone acetylation involved in the activation of stress-related signaling pathways for amyoid-β (A β)production.Human neuroblastoma SH-SY5Y cells were treated by anisomycin, an activator of stress-related MAPKs (JNK and p38 MAPK).A significant increase of intracellular A β level in anisomycin-treated SH-SY5Y cells was observed.The expression of amyloid-β precursor protein APP), β-site APP-cleaving enzyme 1 (BACE1), and presenilin 1 (PS1) was upregulated by demethylation in three gene promoters associated with the reduction of methyltransferases DNMTs).Meanwhile, an enhanced level of global histone H3 acetylation accompanied with upregulation of histone acetylransferases p300/CREB-binding protein (CBP) and downregulation of histone deacetylases (HDACs) was also observed.These findings indicated that the activation of stress-related signaling pathways could result in the increased ranscription of APP, BACE1, and PS1 genes through DNMT-dependent hypomethylation and histone H3 hyperacetylaion, thus leading to A β overproduction.Moreover, our findings provided a novel insight into epigenetic mechanisms by which oxidative stress contributes to the pathogenesis of AD.