LAUSR

Membrane disruption mediated by the accumulation of amyloid-β (Aβ) on cell membranes is central to the pathogenesis of Alzheimer's disease (AD). Cholesterol, an important component of membranes, is well-recognized as a risk factor in AD. It can affect the aggregation and pore formation of Aβ on membranes whereas the specific effects are rather complex, particularly regarding the non-linear response to cholesterol concentrations. Yet, the mechanistic understanding of the role of cholesterol in Aβ-membrane interactions remains incomplete. Herein, we employed microsecond-scale molecular dynamics simulations to investigate the effects of cholesterol on Aβ dimerization in a lipid bilayer containing different molar ratios of cholesterol (0, 20, and 40 mol %). Cholesterol reduces the time required for the formation of stable dimers and exerts dual effects on Aβ-membrane interactions. First, cholesterol promotes the extraction of the C-terminal region from the membrane to water. Consequently, at the ratios of 0 and 20 mol %, peptides are anchored at the membrane-water interface, but they are repelled to water at a ratio of 40 mol % with high structural flexibility. Second, cholesterol weakens Aβ-membrane interactions, thereby enhancing inter-peptide interactions. The former is favorable for dimerization while the latter is not. The balance between two factors eventually leads to a non-monotonic effect on the degree of dimerization, whereby the number of inter-peptide contacts is the largest at a cholesterol ratio of 20 mol %. These results provide atomistic insights into the regulation mechanism of Aβ42 aggregation by cholesterol and help to understand the pathological link between cholesterol and AD.