Impact of Membrane Phospholipids and Exosomes on the Kinetics of Amyloid-β Fibril Assembly

• Published in: Journal of molecular biology 2024-03, Vol.436 (6), p.168464, Article 168464
• Main Authors: Khursheed, Anum, Viles, John H
• Format: Article
• Language: English
• Subjects: Alzheimer disease; Alzheimer’s Disease; brain; cholesterol; exosomes; growth curves; Lipid bilayer; lipid bilayers; lipid metabolism; molecular biology; Nucleation; peptides; phospholipids; Thioflavin-T; zwitterions
• ISSN: 0022-2836; 1089-8638; 1089-8638
• DOI: 10.1016/j.jmb.2024.168464

[Display omitted] •Amyloid assembly in Alzheimer's disease may be influenced by the lipid rich brain.•Anionic phospholipids accelerate fibril assembly by primary nucleation.•Micromolar levels of any phospholipid impacts fibril surface catalysed nucleation.•Physiological, cellular derived exosomes, accelerate Aβ fibril formation.•Alzheimer's related changes in lipid metabolism accelerate fibril formation. Alzheimer's disease (AD) is linked with the self-association of the amyloid-β peptide (Aβ) into oligomers and fibrils. The brain is a lipid rich environment for Aβ to assemble, while the brain membrane composition varies in an age dependent manner, we have therefore monitored the influence of lipid bilayer composition on the kinetics of Aβ40 fibril assembly. Using global-fitting models of fibril formation kinetics, we show that the microscopic rate constant for primary nucleation is influenced by variations in phospholipid composition. Anionic phospholipids and particularly those with smaller headgroups shorten fibril formation lag-times, while zwitterionic phospholipids tend to extend them. Using a physiological vesicle model, we show cellular derived exosomes accelerate Aβ40 and Aβ42 fibril formation. Two distinct effects are observed, the presence of even small amounts of any phospholipid will impact the slope of the fibril growth curve. While subsequent additions of phospholipids only affect primary nucleation with the associated change in lag-times. Heightened anionic phospholipids and cholesterol levels are associated with aging and AD respectively, both these membrane components strongly accelerate primary nucleation during Aβ assembly, making a link between disrupted lipid metabolism and Alzheimer's disease.