| First Author | Park MH | Year | 2012 |
| Journal | J Neuropathol Exp Neurol | Volume | 71 |
| Issue | 2 | Pages | 130-9 |
| PubMed ID | 22249458 | Mgi Jnum | J:318112 |
| Mgi Id | MGI:6858305 | Doi | 10.1097/NEN.0b013e3182432967 |
| Citation | Park MH, et al. (2012) Mutant presenilin 2 increases beta-secretase activity through reactive oxygen species-dependent activation of extracellular signal-regulated kinase. J Neuropathol Exp Neurol 71(2):130-9 |
| abstractText | Senile plaques composed of beta-amyloid (Abeta) are a pathological hallmark of Alzheimer disease. Presenilin 2 (PS2) mutations increase Abeta generation in the brains of Alzheimer disease patients, but the underlying mechanism of Abeta generation by PS2 mutations remains to be clarified. The Abeta 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 beta-secretase and expression of the beta-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), Abeta1-40 and Abeta1-42 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 Abeta generation in neuronal cells expressing mutant PS2. |
