Although oxidative stress is commonly associated with aging (1, 2), patients with Alzheimer disease (AD) 3 often exhibit increased oxidative damage (3-10) and subsequent neuronal loss in -amyloid (A)-rich regions of the brain. The molecular mechanisms by which A contributes to oxidative damage remain unclear (11)(12)(13)(14)(15)(16)(17)(18)(19). Understanding these mechanisms, however, is critical for developing effective methods to manage the disease. One mechanism for A-induced cellular oxidative stress proposes that A peptides interact directly with cellular enzymes responsible for maintaining low physiological levels of reactive oxygen species (ROS) (20 -23). Two potential outcomes from such pathological protein-amyloid interactions are: 1) increased production of ROS, or 2) reduced degradation of ROS.The major ROS in cells are superoxide and the more reactive hydrogen peroxide (H 2 O 2 )-derived hydroxyl radical (24, 25). Both superoxide and H 2 O 2 are primarily produced in the mitochondria (26 -28). A peptides have been shown to accumulate in the mitochondria (29, 30), and, therefore, could exert their detrimental effects through interaction with mitochondrial proteins (23, 31-34). Superoxide is produced by several enzymecatalyzed reactions in the mitochondria (25). Behl et al. (11) however, showed that a broad range of inhibitors of several of these enzymes had no effect on 〈 toxicity in clonal and primary neuronal cell cultures. Furthermore, Zhang et al. (35) reported that superoxide levels in cells were not substantially elevated upon exposure to 〈. These findings suggest that superoxide is not a dominant contributor to 〈 toxicity.On the other hand, 〈-induced cellular increase in H 2 O 2 or its metabolites is strongly correlated with 〈 toxicity (11, 13, 36). H 2 O 2 can be generated by several mitochondrial enzymes including monoamine oxidases, superoxide dismutase, and xanthine oxidase (25). Behl et al. (11) showed that inhibitors of monoamine oxidases and xanthine oxidase had no effect on 〈-induced H 2 O 2 accumulation or 〈 toxicity. Gsell et al. (37) also found that the activity of superoxide dismutase was unaltered in the brains of AD patients. Additionally, Rensink et al. (38) reported that the Dutch mutation of 〈 peptides (HCHWA-D 〈) did not bind directly to superoxide dismutase and Kaminsky et al. (39) reported only a relatively small effect of 〈 on superoxide dismutase activity and H 2 O 2 production upon chronic exposure of rat brains to 〈. These results suggest that 〈 peptides do not significantly affect production of H 2 O 2 in cells. Consequently, these findings imply that 〈-induced oxidative stress may arise from reduced degradation of H 2 O 2 in 〈-challenged cells.Degradation of H 2 O 2 in cells is primarily achieved by the enzymes catalase and glutathione peroxidase (GPx), both inside and outside of the mitochondria (25). Sagara et al. (40) found that cells resistant to 〈 toxicity had elevated levels of catalase and GPx. The activity of both enzymes was redu...