Glutathione cycle impairment mediates Aβ-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 (Abeta). We observed that Abeta 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 rho(0) cells (that lack mitochondrial DNA) in the absence of Abeta showed an increase in ROS production, lipid and protein oxidation, as compared with parental rho(+) cells. Upon Abeta 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 rho(0) cells, in the absence of Abeta, GSH levels were maintained, whereas glutathione reductase and peroxidase activities were increased. The exposure of Ab to rho(0) cells did not induce any change in these parameters. We observed that melatonin prevented caspase activation and DNA fragmentation in rho(+) cells treated with Abeta. Considering the evidence presented, we argue that the glutathione cycle impairment is a key event in Abeta-induced cell toxicity.