Cellular membrane disruption induced by ␤-amyloid (A␤) peptides has been considered one of the major pathological mechanisms for Alzheimer disease. 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 simplified model systems such as the phospholipid liposome. Therefore, separation of these pathways is crucial to achieve an in-depth understanding of the A␤-induced membrane disruption process. This study, which utilized a combination of multiple biophysical techniques, shows that the peptide-to-lipid (P:L) molar ratio is an important factor that regulates the selection of dominant membrane disruption pathways in the presence of 40-residue A␤ peptides in liposomes. Three distinct pathways (fibrillation with membrane content leakage, vesicle fusion, and lipid uptake through a temporarily stable ionic channel) become dominant in model liposome systems under specific conditions. These individual systems are characterized by both the initial states of A␤ peptides and the P:L molar ratio. Our results demonstrated the possibility to generate simplified A␤-membrane model systems with a 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 A␤ aggregation and A␤-membrane interactions may be similar at the molecular level.

Disruption of the synaptic plasma membrane (SPM) induced by the aggregation of β-amyloid (Aβ) peptides has been considered as a potential mechanism for the neurotoxicity of Aβ in Alzheimer's disease (AD). However, the molecular basis of such membrane disruption process remains unclear, mainly because of the severe systematic heterogeneity problem that prevents the high-resolution studies. Our previous studies using a two-component phosphatidylcholine (PC)/phosphatidylglycerol (PG) model liposome showed the presence of Aβ-induced membrane disruptions that were either on the pathway or off the pathway of fibril formation. The present study focuses on a more biologically relevant model membrane with compositions that mimic the outer leaflet of SPMs. The main findings are: (1) the two competing membrane disruption effects discovered in PC/PG liposomes and their general peptide-to-lipid-molar-ratio dependence persist in the more complicated membrane models; (2) the SPM-mimic membrane promotes the formation of certain "on-fibrillation-pathway" intermediates with higher α-helical structural population, which lead to more rapid and significant of membrane content leakage; (3) although the "on-fibrillation-pathway" intermediate structures show dependence on membrane compositions, there seems to be a common final fibril structure grown from different liposomes, suggesting that there may be a predominant fibril structure for 40-residue Aβ (i.e. Aβ) peptides in biologically-relevant membranes. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.

Nonfibrillar β-amyloid (Aβ) oligomers are considered as major neurotoxic species in the pathology of Alzheimer's disease. The presence of Aβ oligomers was shown to cause membrane disruptions in a broad range of model systems. However, the molecular basis of such a disruption process remains unknown. We previously demonstrated that membrane-incorporated 40-residue Aβ (Aβ 40 ) oligomers could form coaggregates with phospholipids. This process occurred more rapidly than the fibrillization of Aβ 40 and led to more severe membrane disruption. The present study probes the time-dependent changes in lipid dynamics, bilayer structures, and peptide-lipid interactions along the time course of the oligomer-induced membrane disruption, using solid-state NMR spectroscopy. Our results suggest the presence of certain intermediate states with phospholipid molecules entering the C-terminal hydrogen-bonding networks of the Aβ 40 oligomeric cores. This work provides insights on the molecular mechanisms of Aβ 40 -oligomer-induced membrane disruption.

Model phospholipid liposomes have been utilized widely to study the molecular interactions between peptides and membrane bilayers. In the mechanistic study of Alzheimer's disease (AD), disruption of neuronal cell membranes has been considered as a major contribution for the β-amyloid (Aβ) peptides' neurotoxicity. However, clear interpretation of the Aβ-induced cellular membrane at high-resolution level is challenging because of the co-existence of multiple pathways. Here we present the generation of simplified model liposome systems that will facilitate the in-depth mechanistic studies. Protocols for the preparation of model liposomes and the characterization of individual membrane disruption effects will be described.