β-Amyloid (1-40) peptide interactions with supported phospholipid membranes: a single-molecule study.

Recent evidence supports the hypothesis that the oligomers formed by the β-amyloid peptide early in its aggregation process are neurotoxic and may feature in Alzheimer's disease. Although the mechanism underlying this neurotoxicity remains unclear, interactions of these oligomers with neuronal membranes are believed to be involved. Identifying the neurotoxic species is challenging because β-amyloid peptides form oligomers at very low physiological concentrations (nM), and these oligomers are highly heterogeneous and metastable. Here, we report the use of single-molecule imaging techniques to study the interactions between β-amyloid (1-40) peptides and supported synthetic model anionic lipid membranes. The evolution of the β-amyloid species on the membranes was monitored for up to several days, and the results indicate an initial tight, uniform, binding of β-amyloid (1-40) peptides to the lipid membranes, followed by oligomer formation in the membrane. At these low concentrations, the behavior at early times during the formation of small oligomers is interpreted qualitatively in terms of the two-state model proposed by H. W. Huang for the interaction between amphipathic peptides and membranes. However, the rate of oligomer formation in the membrane and their size are highly dependent on the concentrations of β-amyloid (1-40) peptides in aqueous solution, suggesting two different pathways of oligomer formation, which lead to drastically different species in the membrane and a departure from the two-state model as the concentration increases.