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.

Automated summary

In this study, solid-state NMR spectroscopy was used to investigate the interactions between β-amyloid (Aβ) peptides and lipids in synaptic plasma membranes. The results revealed the site-specific interactions between Aβ peptides and lipids and demonstrated that these interactions modulate lipid dynamics and influence the structural polymorphisms of Aβ aggregates. These findings provide molecular insights into the early events of fibrillation in biological environments and shed light on the pathogenesis of Alzheimer's disease.