Overexpression of glutathione peroxidase increases the resistance of neuronal cells to Abeta-mediated neurotoxicity.
Senile plaques are neuropathological manifestations in Alzheimer's disease (AD) and are composed mainly of extracellular deposits of amyloid beta-peptide (Abeta). Various data suggest that the accumulation of Abeta may contribute to neuronal degeneration and that Abeta 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 Abeta 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)-de-grading enzyme in neurons, could increase their survival in a cellular model of Abeta-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 Abeta(25-35) or (1-40). Both PC12 and cortical Ad-GPx-infected cells were significantly more resistant to Abeta-induced injury. These data strengthen the hypothesis of a role of H2O2 in the mechanism of Abeta toxicity and highlight the potential of Ad-GPx to reduce Abeta-induced damage to neurons. These findings may have applications in gene therapy for AD.
Barkats
M
M
Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, CNRS UMR C9923, Hôpital de la Pitié Salpêtrière, Paris, France.
Millecamps
S
S
Abrioux
P
P
Geoffroy
M C
MC
Mallet
J
J
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology / Q000821:virology; D003588:Cytopathogenic Effect, Viral; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D005979:Glutathione Peroxidase / Q000096:biosynthesis* / Q000235:genetics; D006861:Hydrogen Peroxide / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000821:virology; D018384:Oxidative Stress / Q000235:genetics*; D016716:PC12 Cells; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D014162:Transfection
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D012333:RNA, Messenger; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase