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Dear AJ, Thacker D, Wennmalm S, Ortigosa-Pascual L, Andrzejewska EA, Meisl G, Linse S, Knowles TPJ
ACS Chem Neurosci 15 (11) 2296-2307 [2024-06-05; online 2024-05-24]
Oligomeric assemblies consisting of only a few protein subunits are key species in the cytotoxicity of neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. Their lifetime in solution and abundance, governed by the balance of their sources and sinks, are thus important determinants of disease. While significant advances have been made in elucidating the processes that govern oligomer production, the mechanisms behind their dissociation are still poorly understood. Here, we use chemical kinetic modeling to determine the fate of oligomers formed in vitro and discuss the implications for their abundance in vivo. We discover that oligomeric species formed predominantly on fibril surfaces, a broad class which includes the bulk of oligomers formed by the key Alzheimer's disease-associated Aβ peptides, also dissociate overwhelmingly on fibril surfaces, not in solution as had previously been assumed. We monitor this "secondary nucleation in reverse" by measuring the dissociation of Aβ42 oligomers in the presence and absence of fibrils via two distinct experimental methods. Our findings imply that drugs that bind fibril surfaces to inhibit oligomer formation may also inhibit their dissociation, with important implications for rational design of therapeutic strategies for Alzheimer's and other amyloid diseases.
Integrated Microscopy Technologies Stockholm [Collaborative]
PubMed 38785363
DOI 10.1021/acschemneuro.4c00127
Crossref 10.1021/acschemneuro.4c00127