RT Journal Article
SR Electronic
T1 Cholesterol in membranes facilitates aggregation of amyloid β protein at physiologically low concentrations
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.09.06.285312
DO 10.1101/2020.09.06.285312
A1 Siddhartha Banerjee
A1 Mohtadin Hashemi
A1 Karen Zagorski
A1 Yuri L. Lyubchenko
YR 2020
UL http://biorxiv.org/content/early/2020/09/07/2020.09.06.285312.abstract
AB 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 directly visualize the aggregation process of Aβ42 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 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 low energy barriers between these conformations facilitate the transition between monomer states and is another factor promoting the self-association of the monomers.Competing Interest StatementThe authors have declared no competing interest.