Structure and membrane interactions of the β-amyloid fragment 25-35 as viewed using spectroscopic approaches

The beta-amyloid fragment peptide 25-35 (A beta(25-35)) is recognized as the cytotoxic sequence of the parent peptide A beta. However, it remains unclear whether its neurotoxicity originates from its fibrillar form, how it interacts with lipid membranes, and whether cholesterol modulates these interactions. These questions have been addressed at a molecular level using various microscopic and spectroscopic techniques. The data show that A beta(25-35) forms protofilaments at pH 7.4 at a concentration of 5 mM in the absence and presence of DMPC/DMPG model membranes. The peptide adopts a predominant aggregated beta-sheet conformation under these conditions. However, as the peptide concentration decreases, the beta-sheet structure tends to disappear for the benefit of beta-turns, suggesting that the peptide association is reversible. The beta-sheet structure formed by A beta(25-35) appears to be atypical and characterized by the absence of intermolecular dipolar coupling and by a parallel strand configuration. The data show that A beta(25-35)-phospholipid interactions are characterized by an increase in the conformational order of the lipid acyl chains and a change in the fluidity/elasticity of the bilayers. Concomitantly, the peptide seems to lose a few beta-sheet structures, which suggests that the interactions between A beta(25-35) and DMPC/DMPG membranes are partly driven by peptide concentration. Interactions indeed seem to occur when part of the peptides is not involved in protofilaments and increase as the proportion of the free peptide species increases. The interactions are very similar in the presence of cholesterol, except that the concentration effect of A beta(25-35) is cancelled, suggesting that Chol limits the penetration of the peptide inside the bilayers.