Aβ Oligomer Dissociation Is Catalyzed by Fibril Surfaces

• DOI: 10.1021/acschemneuro.4c00127
• Publication Date: 2024-05-24T12:01:16Z
• Authors: Alexander J. Dear; Dev Thacker; Stefan Wennmalm; Lei Ortigosa-Pascual; Ewa A. Andrzejewska; Georg Meisl; Sara Linse; Tuomas P. J. Knowles
• Keywords: Oligomer

Oligomeric assemblies consisting of only a few protein subunits are key species in the cytotoxicity neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. Their lifetime solution abundance, governed by balance their sources sinks, thus important determinants disease. While significant advances have been made elucidating processes that govern oligomer production, mechanisms behind dissociation still poorly understood. Here, we use chemical kinetic modeling to determine fate oligomers formed vitro discuss implications for abundance vivo. We discover oligomeric predominantly on fibril surfaces, broad class which includes bulk disease-associated Aβ peptides, also dissociate overwhelmingly not had previously assumed. monitor this "secondary nucleation reverse" measuring Aβ42 presence absence fibrils via two distinct experimental methods. Our findings imply drugs bind surfaces inhibit formation may dissociation, with rational design therapeutic strategies other amyloid