Open AccessMutant Presenilin 2 Increases β-Secretase Activity Through Reactive Oxygen Species–Dependent Activation of Extracellular Signal–Regulated Kinase
Author(s) -
Mi Hee Park,
Dong Young Choi,
Hae Won Jin,
Hyun-jung Yoo,
Jin-Yi Han,
KiWan Oh,
Sang Bae Han,
Dae Yeon Hwang,
Jin Tae Hong
Publication year - 2012
Publication title -
journal of neuropathology and experimental neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.441
H-Index - 164
eISSN - 1554-6578
pISSN - 0022-3069
DOI - 10.1097/nen.0b013e3182432967
Subject(s) - mapk/erk pathway , presenilin , amyloid precursor protein , amyloid precursor protein secretase , mutant , microbiology and biotechnology , extracellular , kinase , senile plaques , reactive oxygen species , chemistry , biology , protein kinase a , biochemistry , alzheimer's disease , medicine , disease , gene
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.