Single Molecule Studies of the Interactions between β-Amyloid 1-40 and Supported Planar Lipid Membrane

Abstract

Recent evidence supports the hypothesis that the early oligomers formed by the β-Amyloid peptide are cytotoxic and may feature in Alzheimer's disease (AD). While the mechanism of this cytotoxicity remains unclear, interactions of these oligomers with neuronal membrane are believed to be involved. Identifying the cytotoxic species is challenging because the β-Amyloid oligomers are extremely heterogeneous, metastable, and form at very low physiological concentrations (nM). In our study, we use single molecule spectroscopy (SMS) to study the interactions between β-Amyloid 1-40 and supported planar lipid membranes. The evolution of β-Amyloid species on lipid membranes were monitored for up to a few days. The results indicate that the interactions between β-Amyloid 1-40 and planar lipid membranes follow three stages. First, a very small fraction of β-Amyloid peptide binds to the membranes with high affinity (Kd < 470pM), covering the membrane surface uniformly and also diffusing within the lipid molecules. In the second stage, β-Amyloid peptides assemble to form oligomers in the membrane. We observed at least two different pathways of oligomer formation, depending on the aqueous β-Amyloid peptide concentration. In the final stage, after prolonged incubation with the lipid membranes, β-Amyloid peptides start forming mesh-like deposits. With the high sensitivity and spatial and temporal resolution of single molecule spectroscopy, we successfully traced the interactions between β-Amyloid 1-40 peptide and planar lipid membranes at the molecular level. Our results are also in agreement with the molecular model of pore-forming peptides suggested by H.W. Huang et al. (1).1. Huang, H.W., F.Y. Chen, and M.T. Lee. 2004. Molecular Mechanism of Peptide-Induced Pores in Membranes. Physical Review Letters. 92:198304.