Secondary Nucleation of Aβ Revealed by Single-Molecule and Computational Approaches.
Fiche publication
Date publication
août 2024
Journal
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
Auteurs
Membres identifiés du Cancéropôle Est :
Dr PICAUD Fabien
Tous les auteurs :
Meyer N, Arroyo N, Roustan L, Janot JM, Charles-Achille S, Torrent J, Picaud F, Balme S
Lien Pubmed
Résumé
Understanding the mechanisms underlying amyloid-β (Aβ) aggregation is pivotal in the context of Alzheimer's disease. This study aims to elucidate the secondary nucleation process of Aβ42 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 Aβ 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 β-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.
Mots clés
amyloid, confocal fluorescence spectroscopy, nanopore, secondary nucleation, single molecule
Référence
Adv Sci (Weinh). 2024 08 19;:e2404916