The iAb5p b-breaker peptide regulates the Ab(25–35) interaction with lipid bilayers through a cholesterol-mediated mechanism

Alzheimer’s disease is characterized by the deposition of aggregates of the b-amyloid peptide (Ab) in the brain. A potential therapeutic strategy for Alzheimer’s disease is the use of synthetic b-sheet breaker pep- tides, which are capable of binding Ab but unable to become part of a b-sheet structure, thus inhibiting the peptide aggregation. Many studies suggest that membranes play a key role in the Ab aggregation; consequently, it is strategic to investigate the interplay between b-sheet breaker peptides and Ab in the presence of lipid bilayers. In this work, we focused on the effect of the b-sheet breaker peptide acetyl-LPFFD-amide, iAb5p, on the interaction of the Ab(25–35) fragment with lipid membranes, studied by Electron Spin Resonance spectroscopy, using spin-labeled membrane components (either phospholip- ids or cholesterol). The ESR results show that iAb5p influences the Ab(25–35) interaction with the bilayer through a cholesterol-mediated mechanism: iAb5p withholds cholesterol in the inner hydrophobic core of the bilayer, making the interfacial region more fluid and capable to accommodate Ab(25–35). As a con- sequence, iAb5p prevents the Ab(25–35) release from the lipid membrane, which is the first step of the b-amyloid aggregation process.