Cupric-amyloid beta 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 Alzheimer's disease. Recently, a number of papers have shown a synergistic neurotoxicity of amyloid beta peptide and cupric ions. We hypothesized that complexes of cupric ions with neurotoxic amyloid beta peptides (Abeta) can stimulate copper-mediated free radical formation. We found that neurotoxic Abeta (1-42), Abeta (1-40), and Abeta (25-35) stimulated copper-mediated oxidation of ascorbate, whereas nontoxic Abeta (40-1) did not. Formation of ascorbate free radical was significantly increased by Abeta (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 beta peptide complexes, implying redox cycling of copper ions. Using the spin-trapping technique, we have shown that toxic amyloid beta peptides led to a 4-fold increase in copper-mediated hydroxyl radical formation. We conclude that toxic Abeta peptides do indeed stimulate copper-mediated oxidation of ascorbate and generation of hydroxyl radicals. Therefore, cupric-amyloid beta peptide-stimulated free radical generation may be involved in the pathogenesis of Alzheimer's disease.
Dikalov
Sergey I
SI
FRIMCORE, Division of Cardiology, Emory Medical School, Atlanta, GA 30322, USA.
Vitek
Michael P
MP
Mason
Ronald P
RP
D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000032:analysis / Q000378:metabolism*; D002570:Ceruloplasmin / Q000494:pharmacology; D003300:Copper / Q000378:metabolism / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals / Q000032:analysis / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000032:analysis / Q000378:metabolism*; D007501:Iron; D010084:Oxidation-Reduction / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism*; D011759:Pyrrolidines / Q000032:analysis / Q000378:metabolism; D013113:Spin Labels
C492269:1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine; D016229:Amyloid beta-Peptides; C045076:Fenton's reagent; D005609:Free Radicals; D010446:Peptide Fragments; D011759:Pyrrolidines; D013113:Spin Labels; D017665:Hydroxyl Radical; D003300:Copper; D006861:Hydrogen Peroxide; D007501:Iron; D002570:Ceruloplasmin; D001205:Ascorbic Acid