The iAβ5p β-breaker peptide regulates the Aβ(25–35) interaction with lipid bilayers through a cholesterol-mediated mechanism

Alzheimer’s disease is characterized by the deposition of aggregates of the β-amyloid peptide (Aβ) in the brain. A potential therapeutic strategy for Alzheimer’s disease is the use of synthetic β-sheet breaker peptides, which are capable of binding Aβ but unable to become part of a β-sheet structure, thus inhibiting the peptide aggregation. Many studies suggest that membranes play a key role in the Aβ aggregation; consequently, it is strategic to investigate the interplay between β-sheet breaker peptides and Aβ in the presence of lipid bilayers. In this work, we focused on the effect of the β-sheet breaker peptide acetyl-LPFFD-amide, iAβ5p, on the interaction of the Aβ(25–35) fragment with lipid membranes, studied by Electron Spin Resonance spectroscopy, using spin-labeled membrane components (either phospholipids or cholesterol). The ESR results show that iAβ5p influences the Aβ(25–35) interaction with the bilayer through a cholesterol-mediated mechanism: iAβ5p withholds cholesterol in the inner hydrophobic core of the bilayer, making the interfacial region more fluid and capable to accommodate Aβ(25–35). As a consequence, iAβ5p prevents the Aβ(25–35) release from the lipid membrane, which is the first step of the β-amyloid aggregation process.

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► iAβ5p shows a significant tendency to deeply penetrates the hydrophobic core of lipid membrane.
► Aβ(25–35) locates in the external region of the membrane causing a re-positioning of CHOL.
► iAβ5p withholds cholesterol in the inner hydrophobic core of the lipid membrane.
► iAβ5p prevents the Aβ(25–35) release from the lipid membrane.