Cholesterol and Clioquinol modulation of A beta(1-42) interaction with phospholipid bilayers and metals.
The beta-sheet plaques that are the most obvious pathological feature of Alzheimer's disease are composed of amyloid-beta peptides and are highly enriched in the metal ions Zn, Fe and Cu. The interaction of the full-length amyloid peptide, A beta(1-42), with phospholipid lipid bilayers was studied in the presence of the metal-chelating drug, Clioquinol (CQ). The effect of cholesterol and metal ions was also determined using solid-state 31P and 2H NMR. CQ modulated the effect of metal ions on the integrity of the bilayer and although CQ perturbed the phospholipid membrane, the bilayer integrity was maintained. Model membranes enriched in cholesterol were studied under conditions of peptide association and incorporation. Solid-state NMR showed that the bilayer integrity was preserved in cholesterol-enriched membranes in comparison to phosphatidylcholine-phosphatidylserine bilayers. Changes in peptide structure, consistent with an increase in beta-sheet, were observed using specifically 13C-labelled A beta(1-42) by magic angle spinning NMR. Results using aligned phosphatidylcholine bilayers and completely 15N-labelled peptide indicated that the peptide aggregated. The results are consistent with oligomeric beta-sheet structured peptides only partially penetrating the bilayer and cholesterol reducing the membrane disruption.
Lau
Tong-Lay
TL
School of Chemistry, Bio21 Institute, The University of Melbourne, Victoria 3010, Australia.
Gehman
John D
JD
Wade
John D
JD
Masters
Colin L
CL
Barnham
Kevin J
KJ
Separovic
Frances
F
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002784:Cholesterol / Q000737:chemistry*; D007464:Clioquinol / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008670:Metals / Q000737:chemistry*; D008954:Models, Biological; D010743:Phospholipids / Q000737:chemistry; D011485:Protein Binding
D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D008670:Metals; D010743:Phospholipids; D007464:Clioquinol; D002784:Cholesterol