Secondary Nucleation of Aβ Revealed by Single-Molecule and Computational Approaches.

Publisher: WILEY-VCH Country of Publication: Germany NLM ID: 101664569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2198-3844 (Electronic) Linking ISSN: 21983844 NLM ISO Abbreviation: Adv Sci (Weinh) Subsets: MEDLINE

Original Publication: Weinheim : WILEY-VCH, [2014]-

Amyloid beta-Peptides*/metabolism ; Amyloid beta-Peptides*/chemistry ; Molecular Dynamics Simulation* ; Alzheimer Disease*/metabolism; Humans ; Spectrometry, Fluorescence/methods ; Single Molecule Imaging/methods

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.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

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ANR-19-CE42-0006 Agence Nationale de la Recherche

Keywords: amyloid; confocal fluorescence spectroscopy; nanopore; secondary nucleation; single molecule

0 (Amyloid beta-Peptides)

Date Created: 20240819 Date Completed: 20241023 Latest Revision: 20241031

20241031

PMC11497034

10.1002/advs.202404916

39159070