Interaction of a β-sheet breaker peptide with lipid membranes.

Aggregation of β-amyloid peptides into senile plaques has been identified as one of the hallmarks of Alzheimer’s disease. An attractive therapeutic strategy for Alzheimer’s disease is the inhibition of the soluble β-amyloid aggregation using synthetic β-sheet breaker peptides that are capable of bindingAβ but are unable tobecome part of aβ-sheet structure. As the early stages of theAβ aggregationprocess are supposed tooccur close to theneuronalmembrane, it is strategic todefine theβ-sheet breaker peptide positioning with respect to lipid bilayers. In thiswork,we have focused on the interaction between the β-sheet breaker peptide acetyl-LPFFD-amide, iAβ5p, and lipid membranes, studied by ESR spectroscopy, using either peptides alternatively labeled at the C- and at the N-terminus or phospholipids spin-labeled in different positions of the acyl chain. Our results show that iAβ5p interacts directly with membranes formed by the zwitterionic phospholipid dioleoyl phosphatidylcholine and this interaction ismodulated by inclusion of cholesterol in the lipid bilayer formulation, in terms of both peptide partition coefficient and the solubilization site. In particular, cholesterol decreases the peptide partition coefficient between themembrane and the aqueous medium. Moreover, in the absence of cholesterol, iAβ5p is located between the outer part of the hydrophobic core and the external hydrophilic layer of the membrane, while in the presence of cholesterol it penetrates more deeply into the lipid bilayer.