Protein misfolding can generate toxic intermediates that cause neurodegenerative diseases such as Alzheimer's disease. The generation of amyloid-β (Aβ) peptide intermediates and fibrils associated with Alzheimer's disease is catalyzed by the surface of these fibrils themselves. However, it has been demonstrated that specifically adapted molecular chaperones, more specifically the BRICHOS protein domain, bind to amyloid fibrils and interrupt this autocatalytic cycle. In this research work, NMR under rapid rotation at the magic angle made it possible to characterize the binding of BRICHOS to the surface of Aβ42 fibrils and therefore to identify a potential site of catalytic aggregation. Based on the NMR results, a molecular mechanism is proposed that provides insight into how toxic nucleation events can be targeted by molecular chaperones.

Link to publication: https://doi.org/10.1038/s41467-024-45192-4

Lyon RMN platform website: https://www.crmn-lyon.fr/