Yan S. intermediate hydrogen peroxide (H2O2). These catalase-A interactions deactivate catalase, resulting in increased cellular levels of H2O2. Furthermore, small molecule inhibitors of catalase-amyloid interactions protect the hydrogen peroxide-degrading activity of catalase in A-rich environments, leading to reduction of the co-localization of catalase and A in cells, inhibition of A-induced increases in cellular levels of H2O2, and reduction of the toxicity of A peptides. These studies, thus, provide evidence for the important role of intracellular catalase-amyloid interactions in A-induced oxidative stress and propose a novel molecular strategy to inhibit such harmful interactions in AD. (11) however, showed that a broad range of inhibitors of several of these enzymes experienced no effect on toxicity in clonal and main neuronal cell cultures. Furthermore, Zhang (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 H2O2 or its metabolites is usually strongly correlated with toxicity (11, 13, 36). H2O2 3-deazaneplanocin A HCl (DZNep HCl) can be generated by several mitochondrial enzymes including monoamine oxidases, superoxide dismutase, and xanthine oxidase (25). Behl (11) showed that inhibitors of monoamine oxidases and xanthine oxidase experienced no effect on -induced H2O2 accumulation or toxicity. Gsell (37) also found that the activity of superoxide dismutase was unaltered in the brains of AD patients. Additionally, Rensink (38) reported that this Dutch mutation of peptides (HCHWA-D ) did not bind directly to superoxide dismutase and Kaminsky (39) reported only a relatively small effect of on superoxide dismutase activity and H2O2 production upon chronic exposure of rat brains to . These results suggest that peptides do not significantly impact production of H2O2 in 3-deazaneplanocin A HCl (DZNep HCl) cells. Consequently, these findings imply that -induced oxidative stress may arise from reduced degradation of H2O2 in -challenged cells. Degradation of H2O2 in cells is usually primarily achieved by the enzymes catalase and glutathione peroxidase (GPx), both inside and outside of the mitochondria (25). Sagara (40) found that cells resistant to toxicity experienced elevated levels of catalase and GPx. The activity of both enzymes was reduced in rat brains exposed to . In particular, Pappolla and Lovell found that catalase was associated with senile plaques in human brain sections from patients with AD (6, 41). Several groups have shown that transfection of cells with catalase (40) or addition of catalase to the extracellular 3-deazaneplanocin A HCl (DZNep HCl) environment of cultured cells guarded cells from toxicity (11, 3-deazaneplanocin A HCl (DZNep HCl) 38). This cytoprotective effect was attributed to a catalase-induced reduction of the H2O2 concentration outside and inside the cells, because H2O2 readily diffuses across cell membranes (25, 43). These observations are consistent 3-deazaneplanocin A HCl (DZNep HCl) with the hypothesis that H2O2, or its metabolites, but not superoxide, play Mouse monoclonal to KSHV ORF26 a dominant role in -induced oxidative stress. Moreover, Milton (21) and our previous work (55) revealed that binds directly to catalase in cell free assays, whereas does not bind to GPx (supplemental Fig. S12). The binding of to catalase prospects to deactivation of the H2O2-degrading activity of catalase in answer (21). Evidence for direct catalase-amyloid interactions and their producing detrimental effects within living cells, however, has not yet been reported. Screening the hypothesis that intracellular catalase- interactions play a significant role in -induced increases in cellular H2O2 may, therefore, provide a crucial and missing mechanistic link between accumulation and oxidative stress in AD. Here, we investigated the effect of catalase-amyloid interactions on A-induced increases in H2O2 and on the producing toxicity in live cells. In these studies, we exposed human neuroblastoma cells to.

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