The lipid peroxidation product 4-hydroxy-2-nonenal (HNE) is proposed to be a toxic factor in the pathogenesis of Alzheimer’s disease. The primary products of lipid peroxidation are phospholipid hydroperoxides and degraded reactive aldehydes, such as HNE, as secondary peroxidation products. In this study, we investigated the role of amyloid-β peptide (Aβ) in the formation of phospholipid hydroperoxides and HNE by copper ion bound to Aβ. The Aβ_<1-42>-Cu^<2+> (1:1 molar ratio) complex showed an activity to form phospholipid hydroperoxides from phospholipid, 1-palmitoyl-2-linoleoyl phosphatidylcholine (PLPC), through Cu^<2+> reduction in the presence of ascorbic acid. The phospholipid hydroperoxides were considered to be racemic mixture of 9-hydroperoxide and 13-hydroperoxide of linoleoyl residue. When Cu^<2+> was bound to two molar equivalents of Aβ_<1-42> (2 Aβ_<1-42>-Cu^<2+>), lipid peroxidation was inhibited. HNE was generated from one of the phospholipid hydroperoxides, 1-palmitoyl-2-(13-hydroperoxy-cis-9, trans-11-octadecadienoyl) phosphatidylcholine (PLPC-OOH), by free Cu^<2+> in the presence of ascorbic acid through Cu^<2+> reduction and degradation of PLPC-OOH. HNE generation was markedly inhibited by equimolar concentrations of Aβ_<1-40> (92%) and Aβ_<1-42> (92%). However, Aβ_<1-42> binding two or three molar equivalents of Cu^<2+> (Aβ_<1-42>-2Cu^<2+>, Aβ_<1-42>-3Cu^<2+>) acted as a pro-oxidant to form HNE from PLPC-OOH. These findings suggest that, at moderate concentrations of copper, Aβ acts primarily as an antioxidant to prevent Cu^<2+>-catalyzed oxidation of biomolecules, but that, in the presence of excess copper, pro-oxidant complexes of Aβ with Cu^<2+> are formed.
