Cholesterol in Membranes Facilitates Aggregation of Amyloid Protein at Physiologically Relevant Concentrations
ACS CHEMICAL NEUROSCIENCE(2021)
Abstract
The formation of amyloid beta (1-42) (A beta 42) oligomers is considered to be a critical step in the development of Alzheimer's 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 test the hypothesis and directly visualize the aggregation process of A beta 42 on the surface of a lipid bilayer depending on the cholesterol presence. 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 results lead to the model for the on-surface aggregation process in which the self-assembly of A beta oligomers is controlled by the lipid composition of cellular membranes.
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Key words
Alzheimer's disease,amyloid beta,amyloid beta oligomers,lipid bilayer,cholesterol,molecular dynamics simulations
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