Lack of glutathione peroxidase-1 exacerbates Abeta-mediated neurotoxicity in cortical neurons.
The aetiologies of Alzheimer's disease (AD) are complex and multifactorial. Current therapies are largely ineffective, as the pathophysiological pathways are poorly understood. Observations in AD autopsies, as well as in vivo and in vitro observations in transgenic mice, have implicated oxidative stress as pathogenic in AD. This study used the Glutathione Peroxidase-1 knockout mouse (Gpx1--/--) model to investigate the role of antioxidant disparity in neuropathologies. Cultured neurons from control and Gpx1--/-- embryos were treated with AD-related peptides and the degree of cell loss compared. Results show that antioxidant disparity makes Gpx1--/-- cells more susceptible to Abeta toxicity. Surrogate replacement of Gpx1 with the reactive oxygen species scavenger N-acetyl cysteine and the Gpx1 mimetic ebselen, reverses the Gpx1--/-- increased susceptibility to Abeta toxicity. Such results support a role for oxidative stress in AD-related neuronal loss. This study is the first to report such findings using the Gpx1--/-- model, and supports a role for oxidative stress as one of the contributing factors, in development of AD-like pathologies.
Crack
P J
PJ
Centre for Functional Genomics and Human Disease, Monash Institute of Reproduction and Development, Monash University, Melbourne, Australia. peter.crack@med.monash.edu.au
Cimdins
K
K
Ali
U
U
Hertzog
P J
PJ
Iannello
R C
RC
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005979:Glutathione Peroxidase / Q000172:deficiency*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000503:physiopathology; D010446:Peptide Fragments / Q000633:toxicity; D013778:Tetrazolium Salts; D013844:Thiazoles; D000094765:Glutathione Peroxidase GPX1
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D013778:Tetrazolium Salts; D013844:Thiazoles; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; C022616:thiazolyl blue; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse