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

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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, which is strikingly similar as observed in vitro. These findings hence provide a molecular understanding of the Aβ42 nucleation process triggered by in vivo-derived Aβ42 propagons, providing a framework for the search for new AD therapeutics.

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Kumar, R., Arroyo-García, L. E., Manchanda, S., Adam, L., Pizzirusso, G., Biverstål, H., … Abelein, A. (2023). Molecular Mechanisms of Amyloid-β Self-Assembly Seeded by In Vivo-Derived Fibrils and Inhibitory Effects of the BRICHOS Chaperone. ACS Chemical Neuroscience. https://doi.org/10.1021/acschemneuro.3c00044

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