Model studies of cholesterol and ascorbate oxidation by copper complexes: relevance to Alzheimer's disease beta-amyloid metallochemistry.
The neurotoxicity of the amyloid-beta peptide (Abeta) is causally linked to Alzheimer's disease (AD) and may be related to the redox chemistry associated with its interactions with copper ions and cholesterol in brain tissue. We have used density functional theory (DFT) calculations to study the mechanism controlling the Abeta/Cu catalyzed oxidation reactions of cholesterol and ascorbate using a model system. The computed results based on a binuclear Cu complex predict that oxidation of cholesterol (yielding 4-cholesten-3-one as a specific product) proceeds at a slow rate when catalyzed by a Abeta/Cu(II)|His-|Cu(II)/Abeta) aggregate. The computed results also suggest that monomeric Abeta/Cu(II) is not able to oxidize cholesterol. DFT also predicted that Abeta will cross-link via covalent dityrosine formation during the oxidation of ascorbate but not during the oxidation of cholesterol. Experimental data were consistent with these predictions.
Haeffner
Fredrik
F
Physics Department, Virginia Commonwealth University, Richmond, VA 23284, USA. fredrikh@nist.gov
Smith
Danielle G
DG
Barnham
Kevin J
KJ
Bush
Ashley I
AI
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000187:drug effects*; D001205:Ascorbic Acid / Q000737:chemistry*; D002784:Cholesterol / Q000737:chemistry*; D003300:Copper / Q000737:chemistry* / Q000633:toxicity*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D046912:Multiprotein Complexes; D010084:Oxidation-Reduction; D018384:Oxidative Stress
D016229:Amyloid beta-Peptides; D046912:Multiprotein Complexes; D003300:Copper; D002784:Cholesterol; D001205:Ascorbic Acid