Cholesterol Modulates the Interaction of β-Amyloid Peptide with Lipid Bilayers

The interaction of an amphiphilic, 40-amino acid beta-amyloid (A beta) peptide with liposomal membranes as a function of sterol mole fraction (X-sterol) was studied based on the fluorescence anisotropy of a site-specific membrane sterol probe, dehydroergosterol (DHE), and fluorescence resonance energy transfer (FRET) from the native Tyr-10 residue of A beta to DHE. Without A beta, peaks or kinks in the DHE anisotropy versus X-sterol plot were detected at X-sterol approximate to 0.25, 0.33, and 0.53. Monomeric A beta preserved these peaks/kinks, but oligomeric A beta suppressed them and created a new DHE anisotropy peak at X-sterol approximate to 0.38. The above critical X-sterol values coincide favorably with the superlattice compositions predicted by the cholesterol superlattice model, suggesting that membrane cholesterol tends to adopt a regular lateral arrangement, or domain formation, in the lipid bilayers. For FRET, a peak was also detected at X-sterol approximate to 0.38 for both monomeric and oligomeric A beta, implying increased penetration of A beta into the lipid bilayer at this sterol mole fraction. We conclude that the interaction of A beta with membranes is affected by the lateral organization of cholesterol, and hypothesize that the formation of an oligomeric A beta/cholesterol domain complex may be linked to the toxicity of A beta in neuronal membranes.