- Journal
- ADVANCED SCIENCE
- Année
- 2024
- Volume
- 11
- Numéro
- 39
- Mois
- OCT
- DOI
- 10.1002/advs.202404916
Abstract
Understanding the mechanisms underlying amyloid-beta (A beta) aggregation is pivotal in the context of Alzheimer's disease. This study aims to elucidate the secondary nucleation process of A beta 42 peptides by combining experimental and computational methods. Using a newly developed nanopipette-based amyloid seeding and translocation assay, confocal fluorescence spectroscopy, and molecular dynamics simulations, the influence of the seed properties on A beta aggregation is investigated. Both fragmented and unfragmented seeds played distinct roles in the formation of oligomers, with fragmented seeds facilitating the formation of larger aggregates early in the incubation phase. The results show that secondary nucleation leads to the formation of oligomers of various sizes and structures as well as larger fibrils structured in beta-sheets. From these findings a mechanism of secondary nucleation involving two types of aggregate populations, one released and one growing on the mother fiber is proposed. Experimental single-molecule techniques and computational methods are used to investigate the secondary nucleation of amyloi-d-beta. By investigating the different oligomer species and the effect of seeds, a mechanism of secondary nucleation involving two types of aggregate populations, one released and one growing on the mother fiber, is proposed. image