---
DOAJ_listed: '1'
OA_place: publisher
OA_type: gold
PlanS_conform: '1'
_id: '21369'
abstract:
- lang: eng
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.'
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.
article_number: '1933'
article_processing_charge: Yes
article_type: original
author:
- first_name: Jing
full_name: Hu, Jing
last_name: Hu
- first_name: Tom
full_name: Scheidt, Tom
last_name: Scheidt
- first_name: Dev
full_name: Thacker, Dev
last_name: Thacker
- first_name: Emil
full_name: Axell, Emil
last_name: Axell
- first_name: Elin
full_name: Stemme, Elin
last_name: Stemme
- first_name: Urszula
full_name: Łapińska, Urszula
last_name: Łapińska
- first_name: Stefan
full_name: Wennmalm, Stefan
last_name: Wennmalm
- first_name: Georg
full_name: Meisl, Georg
last_name: Meisl
- first_name: Samo
full_name: Curk, Samo
id: 031eff0d-d481-11ee-8508-cd12a7a86e5b
last_name: Curk
orcid: 0000-0001-6160-9766
- first_name: Maria
full_name: Andreasen, Maria
last_name: Andreasen
- first_name: Michele
full_name: Vendruscolo, Michele
last_name: Vendruscolo
- first_name: Paolo
full_name: Arosio, Paolo
last_name: Arosio
- first_name: Anđela
full_name: Šarić, Anđela
id: bf63d406-f056-11eb-b41d-f263a6566d8b
last_name: Šarić
orcid: 0000-0002-7854-2139
- first_name: Jeremy D.
full_name: Schmit, Jeremy D.
last_name: Schmit
- first_name: Tuomas P.J.
full_name: Knowles, Tuomas P.J.
last_name: Knowles
- first_name: Emma
full_name: Sparr, Emma
last_name: Sparr
- first_name: Sara
full_name: Linse, Sara
last_name: Linse
- first_name: Thomas C.T.
full_name: Michaels, Thomas C.T.
last_name: Michaels
- first_name: Alexander J.
full_name: Dear, Alexander J.
last_name: Dear
citation:
ama: Hu J, Scheidt T, Thacker D, et al. Structural defects in amyloid-β fibrils
drive secondary nucleation. Nature Communications. 2026;17. doi:10.1038/s41467-026-69377-1
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.
Nature Communications. Springer Nature. https://doi.org/10.1038/s41467-026-69377-1
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.” Nature Communications. Springer Nature, 2026. https://doi.org/10.1038/s41467-026-69377-1.
ieee: J. Hu et al., “Structural defects in amyloid-β fibrils drive secondary
nucleation,” Nature Communications, vol. 17. Springer Nature, 2026.
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.
mla: Hu, Jing, et al. “Structural Defects in Amyloid-β Fibrils Drive Secondary Nucleation.”
Nature Communications, vol. 17, 1933, Springer Nature, 2026, doi:10.1038/s41467-026-69377-1.
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).
date_created: 2026-03-01T23:01:38Z
date_published: 2026-02-20T00:00:00Z
date_updated: 2026-03-02T09:36:48Z
day: '20'
ddc:
- '570'
department:
- _id: AnSa
doi: 10.1038/s41467-026-69377-1
ec_funded: 1
external_id:
pmid:
- '41708600'
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language:
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license: https://creativecommons.org/licenses/by/4.0/
month: '02'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: eba2549b-77a9-11ec-83b8-a81e493eae4e
call_identifier: H2020
grant_number: '802960'
name: 'Non-Equilibrium Protein Assembly: from Building Blocks to Biological Machines'
publication: Nature Communications
publication_identifier:
eissn:
- 2041-1723
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
scopus_import: '1'
status: public
title: Structural defects in amyloid-β fibrils drive secondary nucleation
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legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
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type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
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...