Intracellular proteolytic processing of the beta-amyloid precursor protein is known to yield beta-amyloid peptides [A(beta)] containing 40 or 42 residues that are major constituents of the senile plaques found in Alzheimer's disease and which have been shown to be toxic to cultured neuronal cells and to promote oxidative protein damage in vitro. Because the A(beta)-42 peptide possesses a tight binding site for copper, we are examining the possibility that the pro-oxidant activity of A(beta) is due to metal (copper)-catalyzed reactions. Results of preliminary studies confirm that commercial preparations of A(beta)-42, but not A(beta)-40, contain significant amounts of copper and that its ability to oxidize proteins is enhanced by further addition of cupric copper. These results suggest that the A(beta)-promoted toxicity may involve copper-mediated free radical chemistry. Further studies are designed to test this possibility.