Molecular Mechanisms of Amyloid-β Self-Assembly Seeded by In Vivo-Derived Fibrils and Inhibitory Effects of the BRICHOS Chaperone.

ABSTRACT: Self-replication of amyloid-β-peptide (Aβ) fibril formation is a hallmark in Alzheimer's disease (AD). Detailed insights have been obtained in Aβ self-assembly in vitro, yet whether similar mechanisms are relevant in vivo has remained elusive. Here, we investigated the ability of in vivo-derived Aβ fibrils from two different amyloid precursor protein knock-in AD mouse models to seed Aβ42 aggregation, where we quantified the microscopic rate constants. We found that the nucleation mechanism of in vivo-derived fibril-seeded Aβ42 aggregation can be described with the same kinetic model as that in vitro. Further, we identified the inhibitory mechanism of the anti-amyloid BRICHOS chaperone on seeded Aβ42 fibrillization, revealing a suppression of secondary nucleation and fibril elongation, whic

SUBMITTER: Kumar R 

PROVIDER: S-EPMC10119923 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature