title: PI3K-ERK1/2 activation contributes to extracellular H2O2 generation in amyloid β toxicity.
abstract: Amyloid β peptide (Aβ) induces hydrogen peroxide (H2O2) and superoxide generation, leading to neuronal death. Many studies have shown the involvement of NADPH oxidase, but the isotype-specific role was not assessed. Moreover, the activation status of phosphoinositide 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) 1/2 is unclear in extracellular H2O2 generation. In this paper, we showed that Aβ1-42 induced extracellular H2O2 generation and the resulting cytotoxicity in a concentration-dependent manner. Nox2- and Nox4-specific siRNAs suppressed H2O2 and superoxide generation. LY294002 and U0126, inhibitors of PI3K and ERK1/2, respectively, reduced H2O2 generation in concentration-dependent manners. Furthermore, PI3K activation is responsible for ERK1/2 phosphorylation. An additional increase in H2O2 generation and corresponding cytotoxicity was observed after treatment with Aβ1-42 and glutamate. These results suggest that Aβ1-42 enhances the neuronal vulnerability to oxidative injury in Alzheimer's disease (AD) by increasing H2O2 generation.
authors.affiliation: Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Republic of Korea.
authors.forename: Jong Seong
authors.initials: JS
authors.lastname: Ha
authors.forename: Hye Yeong
authors.initials: HY
authors.lastname: Sung
authors.forename: Heon M
authors.initials: HM
authors.lastname: Lim
authors.forename: Ki-Sun
authors.initials: KS
authors.lastname: Kwon
authors.forename: Sung Sup
authors.initials: SS
authors.lastname: Park
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D020134:Catalytic Domain / Q000235:genetics; D002478:Cells, Cultured; D004789:Enzyme Activation; D005110:Extracellular Space / Q000378:metabolism; D055786:Gene Knockout Techniques; D018698:Glutamic Acid / Q000378:metabolism / Q000633:toxicity; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061251:Primary Cell Culture; D013481:Superoxides / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018698:Glutamic Acid; D006861:Hydrogen Peroxide; D008562:Membrane Glycoproteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013481:Superoxides; C075222:amyloid beta-protein (1-42); C488842:Cybb protein, mouse; C422943:Nox4 protein, mouse