LIPID-BINDING TO AMYLOID BETA-PEPTIDE AGGREGATES - PREFERENTIAL BINDING OF CHOLESTEROL AS COMPARED WITH PHOSPHATIDYLCHOLINE AND FATTY-ACIDS

Amyloid beta-peptide (AP) aggregates are one of the key neuropathologi cal characteristics of Alzheimer's disease. A beta belongs to a group of proteins that aggregate and form beta-sheets, and some of these pro teins bind cholesterol and other lipids. The purpose of the experiment s reported here was to determine if cholesterol, fatty acids, and phos phatidylcholine (PC) would bind to A beta(1-40) and if such binding wo uld be dependent on aggregation of A beta(1-40). Lipid binding was det ermined using fluorescent-labeled lipids. Incubation of A beta(1-40) f or 0, 1, 3, 6, 21, and 24 h resulted in aggregation of the peptide wit h formation of dimers, trimers (1-24 h), and polymers (6-24 h) as dete rmined by sodium dodecyl sulfate-gel electrophoresis. No change in the fluorescence of the lipids was observed when lipids were added to A b eta(1-40) that had been incubated for 0, 1, or 3 h. However, the fluor escence 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) pol ymers (K-D of 3.24 +/- 0.315 x 10(-9) M) was markedly higher as compar ed 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 b eta(1-40) polymers bind lipids and have a higher affinity for choleste rol than PC or saturated fatty acids. Aggregated A beta(1-40) may affe ct lipid transport between cells or remove specific lipids from membra nes, and such effects could contribute to neuronal dysfunction.