Effects of Cholesterol on Amyloid-induced Membrane Poration

The aggregation of amyloid peptides and their interactions with lipid membranes are central to the pathology of several neurodegenerative diseases. Using all-atom molecular dynamics simulations, we investigate how varying cholesterol concentrations (0%, 15%, and 30%) modulate amyloid-induced membrane poration. In cholesterol-free bilayers, pore formation was reproducibly observed in all simulations, whereas the presence of 15% cholesterol significantly reduced pore incidence, and 30% cholesterol entirely suppressed pore formation. Analysis revealed that cholesterol stiffens the bilayer and strongly inhibits peptide-induced perturbations. Furthermore, cholesterol reduced the inter-leaflet mechanical coupling critical for transmembrane beta-sheet formation, a key step in pore initiation. Our findings suggest that increasing cholesterol content protects membranes against amyloid-induced poration, providing a potential molecular basis for the observed reduction in amyloid toxicity in cholesterol-enriched environments. These results offer new insights into the complex role of membrane composition in amyloid-related diseases and highlight cholesterol as a potential modulator of amyloid cytotoxicity.