Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Dynamics of oligomer populations formed during the aggregation of Alzheimer’s Aβ42 peptide

An Author Correction to this article was published on 17 April 2020

This article has been updated


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Experimental procedures for the quantitative measurement of Aβ42 oligomer populations during an ongoing amyloid fibril self-assembly reaction using 3H labelling or MS.
Fig. 2: Kinetic analysis of Aβ42 oligomer populations elucidates the molecular pathways of their dynamics during amyloid aggregation.
Fig. 3: Concentration dependence of the molecular pathways of Aβ42 oligomer dynamics.
Fig. 4: Schematic illustration of the reaction pathways of oligomers during amyloid aggregation and the associated reaction rates determined in this work for Aβ42.

Data availability

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.

Code availability

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.

Change history

  • 17 April 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.


  1. 1.

    Alzheimer’s Association. 2014 Alzheimer’s disease facts and figures. Alzheimers Dement. 10, e47–e92 (2014).

  2. 2.

    Soto, C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat. Rev. Neurosci. 4, 49–60 (2003).

    CAS  Article  Google Scholar 

  3. 3.

    Dobson, C. M. Protein folding and misfolding. Nature 426, 884–890 (2003).

    CAS  Article  Google Scholar 

  4. 4.

    Chiti, F. & Dobson, C. M. Protein misfolding, functional amyloid, and human disease: a summary of progress over the last decade. Annu. Rev. Biochem. 86, 27 (2017).

    CAS  Article  Google Scholar 

  5. 5.

    Knowles, T. P. J., Vendruscolo, M. & Dobson, C. M. The amyloid state and its association with protein misfolding diseases. Nat. Rev. Mol. Cell Biol. 15, 384–396 (2014).

    CAS  Article  Google Scholar 

  6. 6.

    Selkoe, D. J. Folding proteins in fatal ways. Nature 426, 900–904 (2003).

    CAS  Article  Google Scholar 

  7. 7.

    Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

    CAS  Article  Google Scholar 

  8. 8.

    Petkova, A. T. Self-propagating, molecular-level polymorphism in Alzheimer’s amyloid fibrils. Science 307, 262–265 (2005).

    CAS  Article  Google Scholar 

  9. 9.

    Campioni, S. et al. A causative link between the structure of aberrant protein oligomers and their toxicity. Nat. Chem. Biol. 6, 140–147 (2010).

    CAS  Article  Google Scholar 

  10. 10.

    Qiang, W., Yau, W.-M., Lu, J.-X., Collinge, J. & Tycko, R. Structural variation in amyloid-β fibrils from Alzheimer’s disease clinical subtypes. Nature 541, 217–221 (2017).

    CAS  Article  Google Scholar 

  11. 11.

    Cremades, N. et al. Direct observation of the interconversion of normal and toxic forms of α-synuclein. Cell 149, 1048–1059 (2012).

    CAS  Article  Google Scholar 

  12. 12.

    Benilova, I., Karran, E. & De Strooper, B. The toxic Aβ oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat. Neurosci. 15, 349–357 (2012).

    CAS  Article  Google Scholar 

  13. 13.

    Catalano, S. M. et al. The role of amyloid-beta derived diffusible ligands (ADDLs) in Alzheimer’s disease. Curr. Top. Med. Chem. 6, 597–608 (2006).

    CAS  Article  Google Scholar 

  14. 14.

    Lashuel, H. A., Hartley, D., Petre, B. M., Walz, T. & Lansbury, P. T. Jr Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418, 291 (2002).

    CAS  Article  Google Scholar 

  15. 15.

    Knowles, T. P. J. et al. An analytical solution to the kinetics of breakable filament assembly. Science 326, 1533–1537 (2009).

    CAS  Article  Google Scholar 

  16. 16.

    Cohen, S. I. A. et al. Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism. Proc. Natl Acad. Sci. USA 110, 9758–9763 (2013).

    CAS  Article  Google Scholar 

  17. 17.

    Törnquist, M. et al. Secondary nucleation in amyloid formation. Chem. Commun. 54, 8667–8684 (2018).

    Article  Google Scholar 

  18. 18.

    Michaels, T. C. T. et al. Chemical kinetics for bridging molecular mechanisms and macroscopic measurements of amyloid fibril formation. Annu. Rev. Phys. Chem. 69, 273–298 (2018).

    CAS  Article  Google Scholar 

  19. 19.

    Walsh, D. M. et al. A facile method for expression and purification of the Alzheimer’s disease-associated amyloid β-peptide. FEBS J. 276, 1266–1281 (2009).

    CAS  Article  Google Scholar 

  20. 20.

    Szczepankiewicz, O. et al. N-terminal extensions retard Aβ42 fibril formation but allow cross-seeding and coaggregation with Aβ42. J. Am. Chem. Soc. 137, 14673–14685 (2015).

    CAS  Article  Google Scholar 

  21. 21.

    Nasir, I., Linse, S. & Cabaleiro-Lago, C. Fluorescent filter-trap assay for amyloid fibril formation kinetics in complex solutions. ACS Chem. Neurosci. 6, 1436–1444 (2015).

    CAS  Article  Google Scholar 

  22. 22.

    Colvin, M. T. et al. Atomic resolution structure of monomorphic Aβ-42 amyloid fibrils. J. Am. Chem. Soc. 138, 9663–9674 (2016).

    CAS  Article  Google Scholar 

  23. 23.

    Wälti, M. A. et al. Atomic-resolution structure of a disease-relevant Aβ(1–42) amyloid fibril. Proc. Natl Acad. Sci. USA 113, E4976–E4984 (2016).

    Article  Google Scholar 

  24. 24.

    Anwar, J., Khan, S. & Lindfors, L. Secondary crystal nucleation: nuclei breeding factory uncovered. Angew. Chem. Int. Ed. 54, 14681–14684 (2015).

    CAS  Article  Google Scholar 

  25. 25.

    Orgel, L. E. Prion replication and secondary nucleation. Chem. Biol. 3, 413–414 (1996).

    CAS  Article  Google Scholar 

  26. 26.

    Vekilov, P. G. The two-step mechanism of nucleation of crystals in solution. Nanoscale 2, 2346–2357 (2010).

    CAS  Article  Google Scholar 

  27. 27.

    Sear, R. P. The non-classical nucleation of crystals: microscopic mechanisms and applications to molecular crystals, ice and calcium carbonate. Int. Mater. Rev. 57, 328–356 (2012).

    CAS  Article  Google Scholar 

  28. 28.

    Koffie, R. et al. Oligomeric amyloid associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc. Natl Acad. Sci. USA 106, 4012–4017 (2009).

    CAS  Article  Google Scholar 

  29. 29.

    Cohen, S. I. A. et al. A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers. Nat. Struct. Mol. Biol. 22, 207–213 (2015).

    CAS  Article  Google Scholar 

  30. 30.

    Cukalevki, R. et al. The Aβ40 and Aβ42 peptides self-assemble into separate homomolecular fibrils in binary mixtures but cross-react during primary nucleation. Chem. Sci. 6, 4215–4233 (2015).

    Article  Google Scholar 

  31. 31.

    Šarić, A. et al. Physical determinants of the self-replication of protein fibrils. Nat. Phys. 12, 874–880 (2016).

    Article  Google Scholar 

  32. 32.

    Fändrich, M., Fletcher, M. A. & Dobson, C. M. Amyloid fibrils from muscle myoglobin. Nature 410, 165–166 (2001).

    Article  Google Scholar 

  33. 33.

    Allison, J. R., Varnai, P., C. M. Dobson, C. M. & Vendruscolo, M. Determination of the free energy landscape of alpha-synuclein using spin label nuclear magnetic resonance measurements. J. Am. Chem. Soc. 131, 18314–18326 (2009).

    CAS  Article  Google Scholar 

  34. 34.

    Šarić, A., Chebaro, Y. C., Knowles, T. P. J. & Frenkel, D. Crucial role of nonspecific interactions in amyloid nucleation. Proc. Natl Acad. Sci. USA 111, 17869–17874 (2014).

    Article  Google Scholar 

  35. 35.

    Šarić, A., Michaels, T. C. T., Zaccone, A., Knowles, T. P. J. & Frenkel, D. Kinetics of spontaneous filament nucleation via oligomers: insights from theory and simulation. J. Chem. Phys. 145, 211926 (2016).

    Article  Google Scholar 

  36. 36.

    Michaels, T. C. T. et al. Reaction rate theory for supramolecular kinetics: application to protein aggregation. Mol. Phys. 116, 3055–3065 (2018).

    CAS  Article  Google Scholar 

  37. 37.

    Galkin, O. et al. Two-step mechanism of homogeneous nucleation of sickle cell hemoglobin polymers. Biophys. J. 93, 902–913 (2007).

    CAS  Article  Google Scholar 

  38. 38.

    Auer, S., Dobson, C. M. & Vendruscolo, M. Characterization of the nucleation barriers for protein aggregation and amyloid formation. HFSP J. 1, 137–146 (2007).

    CAS  Article  Google Scholar 

  39. 39.

    Lee, C.-T. & Terentjev, E. M. Mechanisms and rates of nucleation of amyloid fibrils. J. Chem. Phys. 147, 105103 (2017).

    Article  Google Scholar 

  40. 40.

    Chen, S. W. et al. Structural characterization of toxic oligomers that are kinetically trapped during alpha-synuclein fibril formation. Proc. Natl Acad. Sci. USA 112, E1994–E2003 (2015).

    CAS  Article  Google Scholar 

  41. 41.

    Garai, K., Posey, A. E., Li, X., Buxbaum, J. N. & Pappu, R. V. Inhibition of amyloid beta fibril formation by monomeric human transthyretin. Protein Sci. 27, 1252–1261 (2018).

    CAS  Article  Google Scholar 

Download references


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).

Author information




All the authors were involved in the design of the study; T.C.T.M. developed the theoretical model and performed the kinetic analysis; S.L. and K.B. performed the experiments; A.Š. and S.C. performed computer simulations; all the authors participated in interpreting the results and writing the paper.

Corresponding authors

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

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

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.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing