Compelling evidence shows a strong correlation between accumulation of neurotoxic â-amyloid (Aâ) 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 Aâ peptides with enzymes responsible for maintaining normal, cellular levels of reactive oxygen species (ROS). Identification of specific, destructive interactions of Aâ peptides with cellular anti-oxidant enzymes would represent an important step toward understanding the pathogenicity of Aâ peptides in AD. This report demonstrates that exposure of human neuroblastoma cells to cytotoxic preparations of aggregated Aâ peptides results in significant intracellular co-localization of Aâ with catalase, an anti-oxidant enzyme responsible for catalyzing the degradation of the ROS intermediate hydrogen peroxide (H(2)O(2)). These catalase-Aâ interactions deactivate catalase, resulting in increased cellular levels of H(2)O(2). Furthermore, small molecule inhibitors of catalase-amyloid interactions protect the hydrogen peroxide-degrading activity of catalase in Aâ-rich environments, leading to reduction of the co-localization of catalase and Aâ in cells, inhibition of Aâ-induced increases in cellular levels of H(2)O(2), and reduction of the toxicity of Aâ peptides. These studies, thus, provide evidence for the important role of intracellular catalase-amyloid interactions in Aâ-induced oxidative stress and propose a novel molecular strategy to inhibit such harmful interactions in AD.
Alzheimer Disease Amyloid