{"author":[{"last_name":"Hu","first_name":"Jing","full_name":"Hu, Jing"},{"last_name":"Scheidt","first_name":"Tom","full_name":"Scheidt, Tom"},{"first_name":"Dev","full_name":"Thacker, Dev","last_name":"Thacker"},{"first_name":"Emil","full_name":"Axell, Emil","last_name":"Axell"},{"last_name":"Stemme","full_name":"Stemme, Elin","first_name":"Elin"},{"first_name":"Urszula","full_name":"Łapińska, Urszula","last_name":"Łapińska"},{"last_name":"Wennmalm","first_name":"Stefan","full_name":"Wennmalm, Stefan"},{"first_name":"Georg","full_name":"Meisl, Georg","last_name":"Meisl"},{"orcid":"0000-0001-6160-9766","full_name":"Curk, Samo","first_name":"Samo","last_name":"Curk","id":"031eff0d-d481-11ee-8508-cd12a7a86e5b"},{"full_name":"Andreasen, Maria","first_name":"Maria","last_name":"Andreasen"},{"first_name":"Michele","full_name":"Vendruscolo, Michele","last_name":"Vendruscolo"},{"first_name":"Paolo","full_name":"Arosio, Paolo","last_name":"Arosio"},{"full_name":"Šarić, Anđela","orcid":"0000-0002-7854-2139","first_name":"Anđela","last_name":"Šarić","id":"bf63d406-f056-11eb-b41d-f263a6566d8b"},{"full_name":"Schmit, Jeremy D.","first_name":"Jeremy D.","last_name":"Schmit"},{"last_name":"Knowles","first_name":"Tuomas P.J.","full_name":"Knowles, Tuomas P.J."},{"last_name":"Sparr","first_name":"Emma","full_name":"Sparr, Emma"},{"first_name":"Sara","full_name":"Linse, Sara","last_name":"Linse"},{"last_name":"Michaels","full_name":"Michaels, Thomas C.T.","first_name":"Thomas C.T."},{"full_name":"Dear, Alexander J.","first_name":"Alexander J.","last_name":"Dear"}],"file":[{"access_level":"open_access","file_size":4821073,"content_type":"application/pdf","creator":"dernst","checksum":"fa2b55b3a0d8978de7d2d061c7ad8779","file_name":"2026_NatureComm_Hu.pdf","date_created":"2026-03-02T09:34:18Z","relation":"main_file","date_updated":"2026-03-02T09:34:18Z","file_id":"21377","success":1}],"publication_status":"published","type":"journal_article","OA_place":"publisher","language":[{"iso":"eng"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publisher":"Springer Nature","doi":"10.1038/s41467-026-69377-1","intvolume":"        17","year":"2026","date_published":"2026-02-20T00:00:00Z","day":"20","DOAJ_listed":"1","oa_version":"Published Version","pmid":1,"title":"Structural defects in amyloid-β fibrils drive secondary nucleation","article_processing_charge":"Yes","PlanS_conform":"1","publication_identifier":{"eissn":["2041-1723"]},"tmp":{"short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png"},"_id":"21369","publication":"Nature Communications","department":[{"_id":"AnSa"}],"date_created":"2026-03-01T23:01:38Z","oa":1,"volume":17,"ddc":["570"],"month":"02","has_accepted_license":"1","article_type":"original","external_id":{"pmid":["41708600"]},"status":"public","quality_controlled":"1","abstract":[{"text":"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.","lang":"eng"}],"project":[{"_id":"eba2549b-77a9-11ec-83b8-a81e493eae4e","call_identifier":"H2020","grant_number":"802960","name":"Non-Equilibrium Protein Assembly: from Building Blocks to Biological Machines"}],"OA_type":"gold","acknowledgement":"This work was supported by the Swedish Research Council (2019-02397 to E.S., 2015-00143 to S.L., and 2022-06641 to S.L. and E.S.), and the GenerationNano project, the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 945378 (S.L. co-PI). We acknowledge support from the Wellcome Trust (T.P.J.K.), the Cambridge Centre for Misfolding Diseases (T.P.J.K.), the BBSRC (T.P.J.K.), the Frances and Augustus Newman Foundation (T.P.J.K.), the ERC PhysProt (agreement n 337969) (T.S., T.P.J.K., S.L.), ETC StG “NEPA” (A.Š. and S.C.), the Royal Society (S.C., A.S.), the ERASMUS Programme (T.S.), and The Danish Council for Independent Research ∣ Natural Sciences (FNU-11-113326) (M.A.). This work was also funded by the Novo Nordisk Foundation (#NNF19OC0054635 to S.L.), ETH Zürich (T.C.T.M.), and the Swiss National Science Foundation (grant no 219703 to A.J.D. and T.C.T.M.). We acknowledge the use of the nano-Characterisation and nano-Manufacturing Research Equipment (nCHREM) facility for access to microscopy instrumentation. We are grateful to the late Professor Sir Christopher Dobson for invaluable conversations regarding the microfluidic diffusional sizing experiments. We are also grateful to Quentin A. E. Peter and Thomas Müller for their guidance on microfluidic device design. The cuvette-filled icon in Fig. 3d is by Servier [https://smart.servier.com/]. It is licensed under CC-BY 3.0 Unported [https://creativecommons.org/licenses/by/3.0/]. The authors would like to acknowledge Umeå Centre for Electron Microscopy (UCEM) for technical assistance and access to electron microscopy. Support was provided by SciLifeLab national Cryo-EM Unit at Umeå University.","scopus_import":"1","citation":{"apa":"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. <i>Nature Communications</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41467-026-69377-1\">https://doi.org/10.1038/s41467-026-69377-1</a>","short":"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).","ieee":"J. Hu <i>et al.</i>, “Structural defects in amyloid-β fibrils drive secondary nucleation,” <i>Nature Communications</i>, vol. 17. Springer Nature, 2026.","ama":"Hu J, Scheidt T, Thacker D, et al. Structural defects in amyloid-β fibrils drive secondary nucleation. <i>Nature Communications</i>. 2026;17. doi:<a href=\"https://doi.org/10.1038/s41467-026-69377-1\">10.1038/s41467-026-69377-1</a>","mla":"Hu, Jing, et al. “Structural Defects in Amyloid-β Fibrils Drive Secondary Nucleation.” <i>Nature Communications</i>, 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>.","ista":"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.","chicago":"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.” <i>Nature Communications</i>. Springer Nature, 2026. <a href=\"https://doi.org/10.1038/s41467-026-69377-1\">https://doi.org/10.1038/s41467-026-69377-1</a>."},"date_updated":"2026-03-02T09:36:48Z","ec_funded":1,"article_number":"1933","file_date_updated":"2026-03-02T09:34:18Z"}