Loading...
Accelerated Alzheimer’s Aβ-42 secondary nucleation chronologically visualized on fibril surfaces
Date
2024
Abstract
Protein fibril surfaces tend to generate toxic oligomers catalytically. To date, efforts to study the accelerated aggregation steps involved with Alzheimer’s disease–linked amyloid-β (Aβ)–42 proteins on fibril surfaces have mainly relied on fluorophore-based analytics. Here, we visualize rare secondary nucleation events on the surface of Aβ-42 fibrils from embryonic to endpoint stages using liquid-based atomic force microscopy. Nanoscale imaging supported by atomic-scale molecular simulations tracked the adsorption and proliferation of oligomeric assemblies at nonperiodically spaced catalytic sites on the fibril surface. Upon confirming that fibril edges are preferential binding sites for oligomers during embryonic stages, the secondary fibrillar size changes were quantified during the growth stages. Notably, a small population of fibrils that displayed higher surface catalytic activity was identified as superspreaders. Profiling secondary fibrils during endpoint stages revealed a nearly threefold increase in their surface corrugation, a parameter we exploit to classify fibril subpop
Supervisor
Description
Publisher
American Association for the Advancement of Science
Citation
Science Advances 10(43)
Collections
Files
Funding code
Funding Information
Synapsis Foundation-Dementia Research Switzerland for financial support (project number: 2022-PI03)