Lipid peroxidation and 4-hydroxy-2-nonenal formation by copper ion bound to amyloid-beta peptide.
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.
Hayashi
Takaaki
T
Hokkaido Institute of Public Health, Kita 19, Nishi 12, Kita-ku, Sapporo 060-0819, Japan.
Shishido
Naomi
N
Nakayama
Kenji
K
Nunomura
Akihiko
A
Smith
Mark A
MA
Perry
George
G
Nakamura
Masao
M
D000447:Aldehydes / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D003300:Copper / Q000494:pharmacology*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism
D000447:Aldehydes; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010713:Phosphatidylcholines; D010743:Phospholipids; C075222:amyloid beta-protein (1-42); C055402:1-palmitoyl-2-linoleoylphosphatidylcholine; D003300:Copper; C027576:4-hydroxy-2-nonenal