Distinct Membrane Disruption Pathways Are Induced by 40-Residue β-Amyloid Peptides.

Abstract Cellular membrane disruption induced by β-amyloid (Aβ) peptides has been considered as one of the major pathological mechanisms for the Alzheimer's disease (AD). Mechanistic studies of the membrane disruption process at a high-resolution level, on the other hand, are hindered by the co-existence of multiple possible pathways, even in the simplified model systems such as the phospholipid liposome. Therefore, separation of these pathways is crucial to achieve in-depth understanding of the Aβ-induced membrane disruption process. Our current studies, which utilize a combination of multiple biophysical techniques, show that the peptide-to-lipid molar ratio (P:L) is an important factor that regulates the selection of dominant membrane-disruption pathways in the presence of 40-residue Aβ peptides in liposomes. Three distinct pathways, the fibrillation with membrane content leakage, the vesicle fusion, and the lipid uptake through a temporarily stable ionic channel, become dominant in model liposome systems with specific conditions. These individual systems are characterized by both the initial states of Aβ peptides and the P:L molar ratio. Our results demonstrated the possibility to generate simplified Aβ-membrane model systems with homogeneous membrane disruption pathway, which will benefit high-resolution mechanistic studies in the future. Fundamentally, the possibility of pathway selection controlled by P:L suggests that the driving forces for the Aβ aggregation and Aβ-membrane interactions may be similar at the molecular level.