title: Epigenetic mechanisms of amyloid-β production in anisomycin-treated SH-SY5Y cells.
abstract: Oxidative stress and inflammation as the pathological components of Alzheimer's disease (AD) have been well understood. Among a diversity of mitogen-activated protein 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 amyloid-β (Aβ) 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 Aβ 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 acetyltransferases 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 transcription of APP, BACE1, and PS1 genes through DNMT-dependent hypomethylation and histone H3 hyperacetylation, thus leading to Aβ overproduction. Moreover, our findings provided a novel insight into epigenetic mechanisms by which oxidative stress contributes to the pathogenesis of AD.
authors.affiliation: Department of Pathology, Capital Medical University, Beijing 100069, China.
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.forename: X
authors.initials: X
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Ren
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.forename: L
authors.initials: L
authors.lastname: Li
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics; D000841:Anisomycin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D011500:Protein Synthesis Inhibitors; D000841:Anisomycin