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

Senile plaques are neuropathological manifestations in Alzheimer's disease (AD) and are composed mainly of extracellular deposits of amyloid beta-pept ide (A beta), Various data suggest that the accumulation of A beta may cont ribute to neuronal degeneration and that A beta neurotoxicity could be medi ated by oxygen free radicals. Removal of free radicals by antioxidant scave ngers or enzymes was found to protect neuronal cells in culture from A beta toxicity, However, the nature of the free radicals involved is still uncle ar. In this study, we investigated whether the neuronal overexpression of g lutathione peroxidase (GPx), the major hydrogen peroxide (H2O2)-degrading e nzyme in neurons, could increase their survival in a cellular model of A be ta-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 r esistant 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 potent ial of Ad-GPx to reduce A beta-induced damage to neurons. These findings ma y have applications in gene therapy for AD.