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

Abstract

The β-amyloid fragment peptide 25–35 (Aβ_25–35) is recognized as the cytotoxic sequence of the parent peptide Aβ. 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 Aβ_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 β-sheet conformation under these conditions. However, as the peptide concentration decreases, the β-sheet structure tends to disappear for the benefit of β-turns, suggesting that the peptide association is reversible. The β-sheet structure formed by Aβ_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 Aβ_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 β-sheet structures, which suggests that the interactions between Aβ_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 Aβ_25–35 is cancelled, suggesting that Chol limits the penetration of the peptide inside the bilayers.