Lipid peroxidation and 4-hydroxy-2-nonenal formation by copper ion bound to amyloid-β peptide

Hokkaido Institute of Public Health, Kita 19, Nishi 12, Kita-ku, Sapporo 060-0819, Japan.
Free Radical Biology and Medicine (Impact Factor: 5.74). 01/2008; 43(11):1552-9. DOI: 10.1016/j.freeradbiomed.2007.08.013
Source: PubMed


The lipid peroxidation product 4-hydroxy-2-nonenal (HNE) is proposed to be a toxic factor in the pathogenesis of Alzheimer disease. The primary products of lipid peroxidation are phospholipid hydroperoxides, and degraded reactive aldehydes, such as HNE, are considered secondary peroxidation products. In this study, we investigated the role of amyloid-beta peptide (A beta) in the formation of phospholipid hydroperoxides and HNE by copper ion bound to A beta. The A beta1-42-Cu2+ (1:1 molar ratio) complex showed an activity to form phospholipid hydroperoxides from a phospholipid, 1-palmitoyl-2-linoleoyl phosphatidylcholine, through Cu2+ reduction in the presence of ascorbic acid. The phospholipid hydroperoxides were considered to be a racemic mixture of 9-hydroperoxide and 13-hydroperoxide of the linoleoyl residue. When Cu2+ was bound to 2 molar equivalents of A beta(1-42) (2 A beta1-42-Cu2+), 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 Cu2+ in the presence of ascorbic acid through Cu2+ reduction and degradation of PLPC-OOH. HNE generation was markedly inhibited by equimolar concentrations of A beta(1-40) (92%) and A beta(1-42) (92%). However, A beta(1-42) binding 2 or 3 molar equivalents of Cu2+ (A beta1-42-2Cu2+, A beta1-42-3Cu2+) acted as a pro-oxidant to form HNE from PLPC-OOH. These findings suggest that, at moderate concentrations of copper, A beta acts primarily as an antioxidant to prevent Cu2+-catalyzed oxidation of biomolecules, but that, in the presence of excess copper, pro-oxidant complexes of A beta with Cu2+ are formed.

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    • "First, since iron and copper are suggested to play an important role in the self-assembly and neurotoxicity of Ab (Atwood et al., 2004; Bush et al., 1994; Exley, 2006; Hayashi et al., 2007; Jobling et al., 2001; Nakamura et al., 2007), Ab toxicity is expectedly attenuated by such chelators (Huang et al., 1999; Opazo et al., 2002; Rottkamp et al., 2001; Schubert & Chevion, 1995). In fact, the ability of Ab to sequestrate redox metals likely explains conflicting in vivo and in vitro reports demonstrating Ab as both oxidant (Behl, Davis, Cole, & Schubert, 1992) and antioxidant (Hayashi et al., 2007; Nakamura et al., 2007; Nunomura et al., 2001; Smith, Casadesus, Joseph, & Perry, 2002). Second, redox metals, as redoxactive centers, lead to free radical generation (Bishop et al., 2002; Castellani et al., 2007; Sayre et al., 2000; Smith et al., 1997) and oxidative stress, which contribute to the initiation and promotion of neurodegeneration (Casadesus et al., 2004; Markesbery, 1997; Perry et al., 1998; Smith et al., 1995). "

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    • ", Cu 2+ binds to A and elicits similar response in terms of activation of A aggregation, H 2 O 2 generation and other oxidative stress-mediated neuronal toxicity [215] [218] [219]. Specifically, Cu 2+ has high binding affinity towards A at His13, His14, His6 and Tyr10 residues [220]. "
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