Overexpression of glutathione peroxidase increases the resistance of neuronal cells to Aβ-mediated neurotoxicity

Senile plaques are neuropathological manifestations in Alzheimer's disease (AD) and are composed mainly of extracellular deposits of amyloid beta-peptide (A beta), Various data suggest that the accumulation of A beta may contribute to neuronal degeneration and that A beta neurotoxicity could be mediated by oxygen free radicals. Removal of free radicals by antioxidant scavengers or enzymes was found to protect neuronal cells in culture from A beta toxicity, However, the nature of the free radicals involved is still unclear. In this study, we investigated whether the neuronal overexpression of glutathione peroxidase (GPx), the major hydrogen peroxide (H2O2)-degrading enzyme in neurons, could increase their survival in a cellular model of A beta-induced neurotoxicity. We infected pheochromocytoma (PC12) cells and rat embryonic cultured cortical neurons with an adenoviral vector encoding GPx (Ad-GPx) prior to exposure to toxic concentrations of A beta(25-35) or (1-40). Both PC12 and cortical Ad-GPx-infected cells were significantly more resistant to A beta-induced injury. These data strengthen the hypothesis of a role of H2O2 in the mechanism of A beta toxicity and highlight the potential of Ad-GPx to reduce A beta-induced damage to neurons. These findings may have applications in gene therapy for AD.