Cholesterol in membranes facilitates aggregation of amyloid β protein at physiologically relevant concentrations

Siddhartha Banerjee, Mohtadin Hashemi, Karen Zagorski, Yuri L. Lyubchenko

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The formation of amyloid β (1-42) (Aβ42) 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 Aβ42 remains unclear. We have previously shown that oligomers assemble at such low Aβ42 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 Aβ42 aggregation, regardless of a low monomer concentration. We used atomic force microscopy (AFM) to test the hypothesis and directly visualize the aggregation process of Aβ42 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 Aβ42 at nanomolar monomer concentration. Quantitative analysis of the AFM data shows that both the number of Aβ42 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 Aβ42. 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 Aβ oligomers is controlled by the lipid composition of cellular membranes.

Original languageEnglish (US)
Pages (from-to)506-516
Number of pages11
JournalACS Chemical Neuroscience
Volume12
Issue number3
DOIs
StatePublished - Feb 3 2021

Keywords

  • Alzheimer’s disease
  • Amyloid β
  • Amyloid β oligomers
  • Cholesterol
  • Lipid bilayer
  • Molecular dynamics simulations

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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