Mutant presenilin 2 increases ß-secretase activity through reactive oxygen species-dependent activation of extracellular signal-regulated kinase.

Senile plaques composed of ß-amyloid (Aß) are a pathological hallmark of Alzheimer disease. Presenilin 2 (PS2) mutations increase Aß generation in the brains of Alzheimer disease patients, but the underlying mechanism of Aß generation by PS2 mutations remains to be clarified. The Aß is generated through the sequential cleavage of amyloid precursor protein by ß- and γ-secretases. Here, we show that the PS2 mutation N141I enhances the activity of ß-secretase and expression of the ß-site amyloid precursor protein cleavage enzyme 1, a major neuronal ß-secretase in the brains of PS2 transgenic mice and in PC12 cells overexpressing mutant PS2. In parallel with the increased activity of ß-secretase, activation of extracellular signal-regulated kinase (ERK), Aß1-40 and Aß1-42 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 ß-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 ß-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 ß-secretase and, thus, an increase of Aß generation in neuronal cells expressing mutant PS2.