Effect of Membrane Cholesterol on the Structure of Alzheimer's Amyloid β Peptide in Lipid Bilayers

Abstract

A hallmark feature of Alzheimer's disease is formation of extracellular plaques of the amyloid β (Aβ) peptide. There is evidence that the Aβ peptide inserts into the membranes of surrounding neuronal cells, causing membrane permeabilization or rupture. The level of cholesterol in membranes has been shown to affect the extent and toxicity of Aβ plaques, as well as the mode of membrane insertion of Aβ and its structure. Here we analyze the effect of cholesterol on the secondary structure of the 40-residue Aβ peptide in artificial lipid bilayers. Multilayers composed of 0.3 mol fraction of 1-palmitoyl-2-oleoyl-phosphatidylglycerol, (0.7 - Xchol) mol fraction of 1-palmitoyl-2-oleoyl-phosphatidylcholine, and Xchol mol fraction of cholesterol were deposited on a germanium plate, with Xchol = 0, 0.05, 0.1, 0.2 and 0.4, containing Aβ at a 1:15 peptide/lipid molar ratio. Fourier transform infrared spectra were collected on lipid-peptide samples under three conditions, i) dry multilayers, ii) humidified with D2O vapors, and iii) in the presence of a bulk D2O-based buffer. In all cases, the amide I bands of the peptide indicated comparable fractions of α-helical and β-sheet structures. Increase of Xchol from 0 to 0.2 resulted in a significant decrease in the β-sheet structure and a slight increase in α-helix content. Further increase in Xchol to 0.4 reversed the β-sheet content and increased the α-helical structure; the latter effect was much stronger in hydrated samples. Considering that cholesterol at Xchol > 0.2 causes a fluid-disordered to fluid-ordered transition in membranes, the observed structural effects may reflect either conformational changes in membrane-bound Aβ peptide or a squeezing-out effect. These possibilities, as well as the effect of cholesterol on membrane permeabilization will elucidate the role of cholesterol in Aβ structure and function.