Distinct thermodynamic signatures of oligomer generation in the aggregation of the amyloid-β peptide


Mapping free-energy landscapes has proved to be a powerful tool for studying reaction mechanisms. Many complex biomolecular assembly processes, however, have remained challenging to access using this approach, including the aggregation of peptides and proteins into amyloid fibrils implicated in a range of disorders. Here, we generalize the strategy used to probe free-energy landscapes in protein folding to determine the activation energies and entropies that characterize each of the molecular steps in the aggregation of the amyloid-β peptide (Aβ42), which is associated with Alzheimer’s disease. Our results reveal that interactions between monomeric Aβ42 and amyloid fibrils during fibril-dependent secondary nucleation fundamentally reverse the thermodynamic signature of this process relative to primary nucleation, even though both processes generate aggregates from soluble peptides. By mapping the energetic and entropic contributions along the reaction trajectories, we show that the catalytic efficiency of Aβ42 fibril surfaces results from the enthalpic stabilization of adsorbing peptides in conformations amenable to nucleation, resulting in a dramatic lowering of the activation energy for nucleation.

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Fig. 1: Kinetics of Aβ42 aggregation from purely monomeric peptide at different temperatures and initial concentrations.
Fig. 2: Kinetics of pre-seeded Aβ42 aggregation at different temperatures and initial monomer concentrations.
Fig. 3: Arrhenius behaviour of the microscopic rate constants for Aβ42 aggregation.
Fig. 4: Activation energies of fibril elongation, primary nucleation and secondary nucleation in Aβ42 amyloid formation.
Fig. 5: Mapping the free-energy landscape for secondary nucleation.


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We thank B. Jönsson and I. André for helpful discussions. We acknowledge financial support from the Schiff Foundation (S.I.A.C.), St John’s College, Cambridge (S.I.A.C.), the Royal Physiographic Society (R.C.), the Research School FLÄK of Lund University (S.L., R.C.), the Swedish Research Council (S.L.) and its Linneaus Centre Organizing Molecular Matter (S.L.), the Crafoord Foundation (S.L.), Alzheimerfonden (S.L.), the European Research Council (S.L.), NanoLund (S.L.), Knut and Alice Wallenberg Foundation (S.L.), Peterhouse, Cambridge (T.C.T.M.), the Swiss National Science Foundation (T.C.T.M.), Magdalene College, Cambridge (A.K.B.), the Leverhulme Trust (A.K.B.), the Royal Society (A.Š.), the Academy of Medical Sciences (A.Š.), the Wellcome Trust (C.M.D., T.P.J.K., A.Š.), and the Centre for Misfolding Diseases (C.M.D., T.P.J.K, M.V.). A.K.B. thanks the Alzheimer Forschung Initiative (AFI).

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S.I.A.C., R.C., T.P.J.K. and S.L. designed the study. R.C., M.T. and S.L. performed the experiments. S.I.A.C., A.K.B., T.C.T.M., A.Š. and T.P.J.K. analysed the data. All authors discussed the results and contributed to writing the manuscript.

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Correspondence to Tuomas P. J. Knowles or Sara Linse.

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Supplementary Text, Supplementary Methods and Supplementary Figs. 1–6

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Cohen, S.I.A., Cukalevski, R., Michaels, T.C.T. et al. Distinct thermodynamic signatures of oligomer generation in the aggregation of the amyloid-β peptide. Nature Chem 10, 523–531 (2018). https://doi.org/10.1038/s41557-018-0023-x

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