Oligomeric species populated during the aggregation of the Aβ42 peptide have been identified as potent cytotoxins linked to Alzheimer’s disease, but the fundamental molecular pathways that control their dynamics have yet to be elucidated. By developing a general approach that combines theory, experiment and simulation, we reveal, in molecular detail, the mechanisms of Aβ42 oligomer dynamics during amyloid fibril formation. Even though all mature amyloid fibrils must originate as oligomers, we found that most Aβ42 oligomers dissociate into their monomeric precursors without forming new fibrils. Only a minority of oligomers converts into fibrillar structures. Moreover, the heterogeneous ensemble of oligomeric species interconverts on timescales comparable to those of aggregation. Our results identify fundamentally new steps that could be targeted by therapeutic interventions designed to combat protein misfolding diseases.
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The authors confirm that all data generated and analysed during this study are included in this published article and its Supplementary Information. Data are also available from the corresponding authors upon request.
All the simulation and data analysis codes are included in this article and its Supplementary Information. Codes are available from the corresponding authors upon request.
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We acknowledge support from Peterhouse (T.C.T.M.), the Swiss National Science foundation (T.C.T.M.), the Royal Society (A.Š.), the Academy of Medical Sciences (A.Š.), the UCL Institute for the Physics of Living Systems (S.C.), Sidney Sussex College (G.M.), the Wellcome Trust (A.Š., M.V., C.M.D. and T.P.J.K.), the Schiff Foundation (A.J.D.), the Cambridge Centre for Misfolding Diseases (M.V., C.M.D. and T.P.J.K.), the BBSRC (C.M.D. and T.P.J.K.), the Frances and Augustus Newman Foundation (T.P.J.K.), the Swedish Research Council (S.L.) and the ERC grant MAMBA (S.L., agreement no. 340890). The research that led to these results received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) through the ERC grant PhysProt (agreement no. 337969).
The authors declare no competing interests.
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Experimental methods, details on computer simulations, definition and solution of mathematical models of oligomer dynamics, details on data analysis, Supplementary Figs. 1–19, Tables 1 and 2, and Video 1.
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Michaels, T.C.T., Šarić, A., Curk, S. et al. Dynamics of oligomer populations formed during the aggregation of Alzheimer’s Aβ42 peptide. Nat. Chem. 12, 445–451 (2020). https://doi.org/10.1038/s41557-020-0452-1
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