Structural defects in amyloid-β fibrils drive secondary nucleation

article Structural defects in amyloid-β fibrils drive secondary nucleation published yes Jing Hu author Tom Scheidt author Dev Thacker author Emil Axell author Elin Stemme author Urszula Łapińska author Stefan Wennmalm author Georg Meisl author Samo Curk author 031eff0d-d481-11ee-8508-cd12a7a86e5b0000-0001-6160-9766 Maria Andreasen author Michele Vendruscolo author Paolo Arosio author Anđela Šarić author bf63d406-f056-11eb-b41d-f263a6566d8b0000-0002-7854-2139 Jeremy D. Schmit author Tuomas P.J. Knowles author Emma Sparr author Sara Linse author Thomas C.T. Michaels author Alexander J. Dear author AnSa department Non-Equilibrium Protein Assembly: from Building Blocks to Biological Machines project Formation of new amyloid fibrils and oligomers from monomeric protein on the surfaces of existing fibrils is an important driver of many disorders such as Alzheimer’s and Parkinson’s diseases. The structural basis of this secondary nucleation process, however, is poorly understood. Here, we ask whether secondary nucleation sites are found predominantly at rare growth defects: irregularities in the fibril core structure incorporated during their original assembly. We first demonstrate using the specific inhibitor of secondary nucleation, Brichos, that secondary nucleation sites on Alzheimer’s disease-associated fibrils composed of Aβ40 and Aβ42 peptides are rare compared to the number of protein molecules they contain. We then grow Aβ40 fibrils under conditions designed to eliminate most growth defects while leaving the regular fibril morphology unchanged, and confirm the latter using cryo-electron microscopy. We measure both the ability of these annealed fibrils to promote secondary nucleation and the stoichiometry of their secondary nucleation sites, finding that both are greatly reduced as predicted. Re-analysis of published data for other proteins suggests that fibril growth defects may also drive secondary nucleation generally across most amyloids. These findings could unlock structure-based drug design of therapeutics that aim to halt amyloid disorders by inhibiting secondary nucleation sites. https://research-explorer.ista.ac.at/download/21369/21377/2026_NatureComm_Hu.pdf application/pdfno Springer Nature2026 eng Nature Communications 2041-1723 4170860010.1038/s41467-026-69377-1 17 Hu J, Scheidt T, Thacker D, Axell E, Stemme E, Łapińska U, Wennmalm S, Meisl G, Curk S, Andreasen M, Vendruscolo M, Arosio P, Šarić A, Schmit JD, Knowles TPJ, Sparr E, Linse S, Michaels TCT, Dear AJ. 2026. Structural defects in amyloid-β fibrils drive secondary nucleation. Nature Communications. 17, 1933. J. Hu et al., “Structural defects in amyloid-β fibrils drive secondary nucleation,” Nature Communications, vol. 17. Springer Nature, 2026. Hu, Jing, Tom Scheidt, Dev Thacker, Emil Axell, Elin Stemme, Urszula Łapińska, Stefan Wennmalm, et al. “Structural Defects in Amyloid-β Fibrils Drive Secondary Nucleation.” Nature Communications. Springer Nature, 2026. <a href="https://doi.org/10.1038/s41467-026-69377-1">https://doi.org/10.1038/s41467-026-69377-1</a>. Hu, Jing, et al. “Structural Defects in Amyloid-β Fibrils Drive Secondary Nucleation.” Nature Communications, vol. 17, 1933, Springer Nature, 2026, doi:<a href="https://doi.org/10.1038/s41467-026-69377-1">10.1038/s41467-026-69377-1</a>. Hu J, Scheidt T, Thacker D, et al. Structural defects in amyloid-β fibrils drive secondary nucleation. Nature Communications. 2026;17. doi:<a href="https://doi.org/10.1038/s41467-026-69377-1">10.1038/s41467-026-69377-1</a> Hu, J., Scheidt, T., Thacker, D., Axell, E., Stemme, E., Łapińska, U., … Dear, A. J. (2026). Structural defects in amyloid-β fibrils drive secondary nucleation. Nature Communications. Springer Nature. <a href="https://doi.org/10.1038/s41467-026-69377-1">https://doi.org/10.1038/s41467-026-69377-1</a> J. Hu, T. Scheidt, D. Thacker, E. Axell, E. Stemme, U. Łapińska, S. Wennmalm, G. Meisl, S. Curk, M. Andreasen, M. Vendruscolo, P. Arosio, A. Šarić, J.D. Schmit, T.P.J. Knowles, E. Sparr, S. Linse, T.C.T. Michaels, A.J. Dear, Nature Communications 17 (2026). 213692026-03-01T23:01:38Z2026-03-02T09:36:48Z