Early stage β-amyloid-membrane interactions modulate lipid dynamics and influence structural interfaces and fibrillation

Molecular interactions between beta-amyloid (A beta) peptide and membranes contribute to the neuronal toxicity of A beta and the pathology of Alzheimer's disease. Neuronal plasma membranes serve as biologically relevant environments for the A beta aggregation process as well as affect the structural polymorphisms of A beta aggregates. However, the nature of these interactions is unknown. Here, we utilized solid-state NMR spectroscopy to explore the site-specific interactions between A beta peptides and lipids in synaptic plasma membranes at the membraneassociated nucleation stage. The key results show that different segments in the hydrophobic sequence of A beta initiate membrane binding and interstrand assembling. We demonstrate early stage A beta-lipid interactions modulate lipid dynamics, leading to more rapid lipid headgroup motion and reduced lateral diffusive motion. These early events influence the structural polymorphisms of yielded membrane-associated A beta fibrils with distinct C-terminal quaternary interface structure compared to fibrils grown in aqueous solutions. Based on our results, we propose a schematic mechanism by which A beta-lipid interactions drive membrane-associated nucleation processes, providing molecular insights into the early events of fibrillation in biological environments.