Cupric–amyloid β peptide complex stimulates oxidation of ascorbate and generation of hydroxyl radical

A growing body of evidence supports an important role for oxidative stress in the pathogenesis of Alzheimerʹs disease. Recently, a number of papers have shown a synergistic neurotoxicity of amyloid β peptide and cupric ions. We hypothesized that complexes of cupric ions with neurotoxic amyloid β peptides (Aβ) can stimulate copper-mediated free radical formation. We found that neurotoxic Aβ (1-42), Aβ (1-40), and Aβ (25-35) stimulated copper-mediated oxidation of ascorbate, whereas nontoxic Aβ (40-1) did not. Formation of ascorbate free radical was significantly increased by Aβ (1-42) in the presence of ceruloplasmin. Once cupric ion is reduced to cuprous ion, it can be oxidized by oxygen to generate superoxide radical or it can react with hydrogen peroxide to form hydroxyl radical. Hydrogen peroxide greatly increased the oxidation of cyclic hydroxylamines and ascorbate by cupric–amyloid β peptide complexes, implying redox cycling of copper ions. Using the spin-trapping technique, we have shown that toxic amyloid β peptides led to a 4-fold increase in copper-mediated hydroxyl radical formation. We conclude that toxic Aβ peptides do indeed stimulate copper-mediated oxidation of ascorbate and generation of hydroxyl radicals. Therefore, cupric–amyloid β peptide-stimulated free radical generation may be involved in the pathogenesis of Alzheimerʹs disease.