title: Mutant presenilin 2 increases β-secretase activity through reactive oxygen species-dependent activation of extracellular signal-regulated kinase.
abstract: Senile plaques composed of β-amyloid (Aβ) are a pathological hallmark of Alzheimer disease. Presenilin 2 (PS2) mutations increase Aβ generation in the brains of Alzheimer disease patients, but the underlying mechanism of Aβ generation by PS2 mutations remains to be clarified. The Aβ is generated through the sequential cleavage of amyloid precursor protein by β- and γ-secretases. Here, we show that the PS2 mutation N141I enhances the activity of β-secretase and expression of the β-site amyloid precursor protein cleavage enzyme 1, a major neuronal β-secretase in the brains of PS2 transgenic mice and in PC12 cells overexpressing mutant PS2. In parallel with the increased activity of β-secretase, activation of extracellular signal-regulated kinase (ERK), Aβ1-40 and Aβ1-42 levels, generation of reactive oxygen species, and lipid peroxidation were higher in the mutant mouse neurons and the PC12 cells. Colocalization of phosphorylated ERK (phospho-ERK) and β-site amyloid precursor protein cleavage enzyme 1 with hydroxynonenal-histidine was found in the mutant brains. An ERK inhibitor U0126 and an antioxidant N-acetylcysteine prevented the expression and activity of β-secretase, ERK activation, and reactive oxygen species generation in both neurons and PC12 cells expressing mutant PS2 in a dose-dependent manner. Together, these data suggest that oxidative stress-mediated ERK activation contributes to increases in β-secretase and, thus, an increase of Aβ generation in neuronal cells expressing mutant PS2.
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Korea.
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Park
authors.forename: Dong Young
authors.initials: DY
authors.lastname: Choi
authors.forename: Hae Won
authors.initials: HW
authors.lastname: Jin
authors.forename: Hwan Soo
authors.initials: HS
authors.lastname: Yoo
authors.forename: Jin-Yi
authors.initials: JY
authors.lastname: Han
authors.forename: Ki-Wan
authors.initials: KW
authors.lastname: Oh
authors.forename: Sang Bae
authors.initials: SB
authors.lastname: Han
authors.forename: Dae Yeun
authors.initials: DY
authors.lastname: Hwang
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D015227:Lipid Peroxidation / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D010446:Peptide Fragments / Q000378:metabolism; D053766:Presenilin-2 / Q000172:deficiency / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D053766:Presenilin-2; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D048049:Extracellular Signal-Regulated MAP Kinases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human