Interaction of a beta-sheet breaker peptide with lipid membranes.
Aggregation of beta-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 beta-amyloid aggregation using synthetic beta-sheet breaker peptides that are capable of binding Abeta but are unable to become part of a beta-sheet structure. As the early stages of the Abeta aggregation process are supposed to occur close to the neuronal membrane, it is strategic to define the beta-sheet breaker peptide positioning with respect to lipid bilayers. In this work, we have focused on the interaction between the beta-sheet breaker peptide acetyl-LPFFD-amide, iAbeta5p, 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 iAbeta5p interacts directly with membranes formed by the zwitterionic phospholipid dioleoyl phosphatidylcholine and this interaction is modulated 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 the membrane and the aqueous medium. Moreover, in the absence of cholesterol, iAbeta5p 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.
Vitiello
Giuseppe
G
Dipartimento di Chimica "Paolo Corradini", Università di Napoli "Federico II" Complesso di Monte S. Angelo, Via Cinthia, I-80126 Napoli, Italy.
Grimaldi
Manuela
M
Ramunno
Anna
A
Ortona
Ornella
O
De Martino
Giovanni
G
D'Ursi
Anna Maria
AM
D'Errico
Gerardino
G
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D008563:Membrane Lipids; D010446:Peptide Fragments; C474023:iAbeta5 peptide