Glutathione cycle impairment mediates A beta-induced cell toxicity.
Alzheimer's disease is widely held to be associated with oxidative stress due, in part, to the action of amyloid beta-peptide (A beta). We observed that A beta 25-35 induced an increase in reactive oxygen species (ROS) in NT2 rho+ cells, leading to protein and lipid oxidation. This oxidative status was partially prevented by the antioxidants, vitamin E, reduced glutathione, and by melatonin. However, NT2 rho0 cells (that lack mitochondrial DNA) in the absence of A beta showed an increase in ROS production, lipid and protein oxidation, as compared with parental rho+ cells. Upon A beta 25-35 treatment, in rho+ cells, a decrease in glutathione reductase activity and in GSH levels was observed, whereas glutathione peroxidase activity was shown to be increased. In NT2 rho0 cells, in the absence of A beta, GSH levels were maintained, whereas glutathione reductase and peroxidase activities were increased. The exposure of A beta to rho0 cells did not induce any change in these parameters. We observed that melatonin prevented caspase activation and DNA fragmentation in rho+ cells treated with A beta. Considering the evidence presented, we argue that the glutathione cycle impairment is a key event in A beta-induced cell toxicity.
Cardoso
Sandra M
SM
Center for Neuroscience and Cellular Biology of Coimbra, University of Coimbra, 304-504 Coimbra, Portugal.
Oliveira
Catarina R
CR
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation; D004789:Enzyme Activation; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D050356:Lipid Metabolism; D015227:Lipid Peroxidation; D008954:Models, Biological; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D017382:Reactive Oxygen Species; D013997:Time Factors; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D010455:Peptides; D017382:Reactive Oxygen Species; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D020169:Caspases; D005978:Glutathione; D010100:Oxygen