Role of Cholesterol on Binding of Amyloid Fibrils with Lipid Bilayers

Abstract

The aggregation of amyloid-beta proteins into soluble oligomers and fibril deposits is believed to trigger the molecular processes accounting for Alzheimer's disease. In addition, levels of cholesterol, which is an important component of the neuron plasma membrane, are elevated in the brain of Alzheimer's patients and they correlate with the development of the disease in mid-life individuals. A possible explanations for this correlation is that cholesterol affects binding of Abeta proteins to lipid bilayer as this process was shown to have a deleterious effect on neurons. Accordingly, experimental studies have shown that amyloid-beta fibrils bind more strongly to lipid bilayers containing higher cholesterol levels. The molecular mechanism of the process is, however, not well understood. Here, we perform extensive molecular dynamics simulations to investigate the role of cholesterol on fibril-bilayer binding. In particular, we compute the number of binding events as a function of cholesterol level. We find that binding events are driven by electrostatic interactions, they have a longer life-time and occur more frequently with increased cholesterol level. An explanation of these results at the molecular level is provided based on the distribution of residues on the fibril surface.