Cholesterol in membranes facilitates aggregation of amyloid beta protein at physiologically low concentrations

Abstract

The formation of amyloid {beta} (1-42) (A{beta}42) oligomers is considered to be a critical step in the development of Alzheimers disease (AD). However, the mechanism underlying this process at physiologically low concentrations of A{beta}42 remains unclear. We have previously shown that oligomers assemble at such low A{beta}42 monomer concentrations in vitro on phospholipid membranes. We hypothesized that membrane composition is the factor controlling the aggregation process. Accumulation of cholesterol in membranes is associated with AD development, suggesting that insertion of cholesterol into membranes may initiate the A{beta}42 aggregation, regardless of a low monomer concentration. We used atomic force microscopy (AFM) to directly visualize the aggregation process of A{beta}42 on the surface of a lipid bilayer containing cholesterol. Time-lapse AFM imaging unambiguously demonstrates that cholesterol in the lipid bilayer significantly enhances the aggregation process of A{beta}42 at nanomolar monomer concentration. Quantitative analysis of the AFM data shows that both the number of A{beta}42 oligomers and their sizes grow when cholesterol is present. Importantly, the aggregation process is dynamic, so the aggregates assembled on the membrane can dissociate from the bilayer surface into the bulk solution. Computational modeling demonstrated that the lipid bilayer containing cholesterol had an elevated affinity to A{beta}42. Moreover, monomers adopted the aggregation-prone conformations present in amyloid fibrils. The low energy barriers between these conformations facilitate the transition between monomer states and is another factor promoting the self-association of the monomers.