Lipid binding to amyloid beta-peptide aggregates: preferential binding of cholesterol as compared with phosphatidylcholine and fatty acids.
Amyloid beta-peptide (A beta) aggregates are one of the key neuropathological characteristics of Alzheimer's disease. A beta belongs to a group of proteins that aggregate and form beta-sheets, and some of these proteins bind cholesterol and other lipids. The purpose of the experiments reported here was to determine if cholesterol, fatty acids, and phosphatidylcholine (PC) would bind to A beta(1-40) and if such binding would be dependent on aggregation of A beta(1-40). Lipid binding was determined using fluorescent-labeled lipids. Incubation of A beta(1-40) for 0, 1, 3, 6, 21, and 24 h resulted in aggregation of the peptide with formation of dimers, trimers (1-24 h), and polymers (6-24 h) as determined by sodium dodecyl sulfate-gel electrophoresis. No change in the fluorescence of the lipids was observed when lipids were added to A beta(1-40) that had been incubated for 0, 1, or 3 h. However, the fluorescence intensities of cholesterol, saturated fatty acids, and PC were significantly increased (p < 0.0001) when added to A beta(1-40) that had been incubated for 6, 21, and 24 h in which A beta(1-40) polymers were detected. The binding affinity of cholesterol to A beta(1-40) polymers (K(D) of 3.24 +/- 0.315 x 10(-9) M) was markedly higher as compared with the other lipids (stearic acid, 9.42 +/- 0.41 x 10(-8) M; PC, 7.07 +/- 0.12 x 10(-7) M). The results of this study indicate that A beta(1-40) polymers bind lipids and have a higher affinity for cholesterol than PC or saturated fatty acids. Aggregated A beta(1-40) may affect lipid transport between cells or remove specific lipids from membranes, and such effects could contribute to neuronal dysfunction.
Avdulov
N A
NA
Geriatric Research, Education and Clinical Center, V.A. Medical Center, and Department of Pharmacology, University of Minnesota, School of Medicine, Minneapolis 55417, U.S.A.
Chochina
S V
SV
Igbavboa
U
U
Warden
C S
CS
Vassiliev
A V
AV
Wood
W G
WG
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001667:Binding, Competitive; D002784:Cholesterol / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D005227:Fatty Acids / Q000378:metabolism*; D005456:Fluorescent Dyes; D050356:Lipid Metabolism; D008823:Micelles; D010069:Oxadiazoles; D010713:Phosphatidylcholines / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D005227:Fatty Acids; D005456:Fluorescent Dyes; D008823:Micelles; D010069:Oxadiazoles; D010713:Phosphatidylcholines; D002784:Cholesterol