Inhibitors of Catalase-Amyloid Interactions Protect Cells from β-Amyloid-Induced Oxidative Stress and Toxicity

Compelling evidence shows a strong correlation between accumulation of neurotoxic beta-amyloid (A beta) peptides and oxidative stress in the brains of patients afflicted with Alzheimer disease (AD). One hypothesis for this correlation involves the direct and harmful interaction of aggregated A beta peptides with enzymes responsible for maintaining normal, cellular levels of reactive oxygen species (ROS). Identification of specific, destructive interactions of A beta peptides with cellular anti-oxidant enzymes would represent an important step toward understanding the pathogenicity of A beta peptides in AD. This report demonstrates that exposure of human neuroblastoma cells to cytotoxic preparations of aggregated A beta peptides results in significant intracellular co-localization of A beta with catalase, an anti-oxidant enzyme responsible for catalyzing the degradation of the ROS intermediate hydrogen peroxide (H2O2). These catalase-A beta 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 beta-rich environments, leading to reduction of the co-localization of catalase and A beta in cells, inhibition of A beta-induced increases in cellular levels of H2O2, and reduction of the toxicity of A beta peptides. These studies, thus, provide evidence for the important role of intracellular catalase-amyloid interactions in A beta-induced oxidative stress and propose a novel molecular strategy to inhibit such harmful interactions in AD.