Abstract
Nonspecific membrane disruption is considered a plausible mechanism for the cytotoxicity induced by β-amyloid (Aβ) aggregates. In scenarios of high local Aβ concentrations, a two-step membrane fragmentation model has been proposed. Initially, membrane-embedded Aβ oligomeric aggregates form, followed by membrane fragmentation. However, the key molecular-level interactions between Aβ oligomeric aggregates and lipids that drive the second-stage membrane fragmentation remain unclear. This study monitors the time-dependent changes in lipid dynamics and water accessibility of model liposomes during Aβ-induced membrane fragmentation. Our results indicate that lipid dynamics on the nanosecond to microsecond time scale undergo rapid acceleration upon initial incubation with membrane-incorporated Aβ oligomeric aggregates, followed by a slow deceleration process. Concurrently, lipid headgroups become less accessible to water. Both observations suggest a carpet-like mechanism of membrane disruption for the Aβ-induced membrane fragmentation process.