Hydrogen peroxide promotes Aβ production through JNK-dependent activation of γ-secretase

Accumulation of senile plaques composed of amyloid beta-peptide (A beta) is a pathological hallmark of Alzheimer disease ( AD), and A beta is generated through the sequential cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase. Although oxidative stress has been implicated in the AD pathogenesis by inducing A beta production, the underlying mechanism remains elusive. Here we show that the pro-oxidant H2O2 promotes A beta production through c-Jun N-terminal kinase (JNK)-dependent activation of gamma-secretase. Treatment with H2O2 induced significant increase in the levels of intracellular and secreted A beta in human neuroblastoma SH-SY5Y cells. Although gamma-secretase-mediated cleavage of APP or C99 was enhanced upon H2O2 treatment, expression of APP or its alpha/beta-secretase-mediated cleavage was not affected. Silencing of the stress-activated JNK by small interfering RNA or the specific JNK inhibitor SP600125 reduced H2O2-induced gamma-secretase-mediated cleavage of APP. JNK activity was augmented in human brain tissues from AD patients and active JNK located surrounding the senile plaques in the brain of AD model mouse. Our data suggest that oxidative stress-activated JNK may contribute to senile plaque expansion through the promotion of gamma-secretase-mediated APP cleavage and A beta production.