Mutant Presenilin 2 Increases beta-Secretase Activity Through Reactive Oxygen Species-Dependent Activation of Extracellular Signal-Regulated Kinase

Title
Mutant Presenilin 2 Increases beta-Secretase Activity Through Reactive Oxygen Species-Dependent Activation of Extracellular Signal-Regulated Kinase
Author(s)
최동영박미희[박미희]진혜원[진혜원]유환수[유환수]한진이[한진이]오기완[오기완]한상배[한상배]황대윤[황대윤]홍진태[홍진태]
Keywords
AMYLOID PRECURSOR PROTEIN; NEURONAL CELL-DEATH; INCREASED OXIDATIVE STRESS; DOUBLE-KNOCKOUT MICE; ALZHEIMERS-DISEASE; A-BETA; GAMMA-SECRETASE; BACE1; EXPRESSION; PATHWAYS
Issue Date
201202
Publisher
LIPPINCOTT WILLIAMS & WILKINS
Citation
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, v.71, no.2, pp.130 - 139
Abstract
Senile plaques composed of beta-amyloid (A beta) are a pathological hallmark of Alzheimer disease. Presenilin 2 (PS2) mutations increase A beta generation in the brains of Alzheimer disease patients, but the underlying mechanism of A beta generation by PS2 mutations remains to be clarified. The A beta is generated through the sequential cleavage of amyloid precursor protein by beta- and gamma-secretases. Here, we show that the PS2 mutation N141I enhances the activity of A-secretase and expression of the A-site amyloid precursor protein cleavage enzyme 1, a major neuronal beta-secretase in the brains of PS2 transgenic mice and in PC12 cells overexpressing mutant PS2. In parallel with the increased activity of beta-secretase, activation of extracellular signal-regulated kinase (ERK), A beta 1-40 and A beta 1-42 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 beta-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 beta-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 beta-secretase and, thus, an increase of A beta generation in neuronal cells expressing mutant PS2.
URI
http://hdl.handle.net/YU.REPOSITORY/29857http://dx.doi.org/10.1097/NEN.0b013e3182432967
ISSN
0022-3069
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약학대학 > 약학부 > Articles
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