Mechanism of Secondary Nucleation at the Single Fibril Level from Direct Observations of Aβ42 Aggregation
(2021) In Journal of the American Chemical Society 143. p.16621-16629- Abstract
The formation of amyloid fibrils and oligomers is a hallmark of several neurodegenerative disorders, including Alzheimer's disease (AD), and contributes to the disease pathway. To progress our understanding of these diseases at a molecular level, it is crucial to determine the mechanisms and rates of amyloid formation and replication. In the context of AD, the self-replication of aggregates of the Aβ42 peptide by secondary nucleation, leading to the formation of new aggregates on the surfaces of existing ones, is a major source of both new fibrils and smaller toxic oligomeric species. However, the core mechanistic determinants, including the presence of intermediates, as well as the role of heterogeneities in the fibril population, are... (More)
The formation of amyloid fibrils and oligomers is a hallmark of several neurodegenerative disorders, including Alzheimer's disease (AD), and contributes to the disease pathway. To progress our understanding of these diseases at a molecular level, it is crucial to determine the mechanisms and rates of amyloid formation and replication. In the context of AD, the self-replication of aggregates of the Aβ42 peptide by secondary nucleation, leading to the formation of new aggregates on the surfaces of existing ones, is a major source of both new fibrils and smaller toxic oligomeric species. However, the core mechanistic determinants, including the presence of intermediates, as well as the role of heterogeneities in the fibril population, are challenging to determine from bulk aggregation measurements. Here, we obtain such information by monitoring directly the time evolution of individual fibrils by TIRF microscopy. Crucially, essentially all aggregates have the ability to self-replicate via secondary nucleation, and the amplification of the aggregate concentration cannot be explained by a small fraction of "superspreader"fibrils. We observe that secondary nucleation is a catalytic multistep process involving the attachment of soluble species to the fibril surface, followed by conversion/detachment to yield a new fibril in solution. Furthermore, we find that fibrils formed by secondary nucleation resemble the parent fibril population. This detailed level of mechanistic insights into aggregate self-replication is key in the rational design of potential inhibitors of this process.
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- author
- Zimmermann, Manuela R. ; Bera, Subhas C. ; Meisl, Georg ; Dasadhikari, Sourav ; Ghosh, Shamasree ; Linse, Sara LU ; Garai, Kanchan and Knowles, Tuomas P.J.
- organization
- publishing date
- 2021-09
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of the American Chemical Society
- volume
- 143
- article number
- 07228
- pages
- 9 pages
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- scopus:85117177290
- pmid:34582216
- ISSN
- 0002-7863
- DOI
- 10.1021/jacs.1c07228
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2021 American Chemical Society.
- id
- d8cdb8ae-5db9-4c56-8713-e5ce73d1f462
- date added to LUP
- 2021-10-27 12:50:14
- date last changed
- 2024-06-16 21:56:04
@article{d8cdb8ae-5db9-4c56-8713-e5ce73d1f462,
abstract = {{<p>The formation of amyloid fibrils and oligomers is a hallmark of several neurodegenerative disorders, including Alzheimer's disease (AD), and contributes to the disease pathway. To progress our understanding of these diseases at a molecular level, it is crucial to determine the mechanisms and rates of amyloid formation and replication. In the context of AD, the self-replication of aggregates of the Aβ42 peptide by secondary nucleation, leading to the formation of new aggregates on the surfaces of existing ones, is a major source of both new fibrils and smaller toxic oligomeric species. However, the core mechanistic determinants, including the presence of intermediates, as well as the role of heterogeneities in the fibril population, are challenging to determine from bulk aggregation measurements. Here, we obtain such information by monitoring directly the time evolution of individual fibrils by TIRF microscopy. Crucially, essentially all aggregates have the ability to self-replicate via secondary nucleation, and the amplification of the aggregate concentration cannot be explained by a small fraction of "superspreader"fibrils. We observe that secondary nucleation is a catalytic multistep process involving the attachment of soluble species to the fibril surface, followed by conversion/detachment to yield a new fibril in solution. Furthermore, we find that fibrils formed by secondary nucleation resemble the parent fibril population. This detailed level of mechanistic insights into aggregate self-replication is key in the rational design of potential inhibitors of this process.</p>}},
author = {{Zimmermann, Manuela R. and Bera, Subhas C. and Meisl, Georg and Dasadhikari, Sourav and Ghosh, Shamasree and Linse, Sara and Garai, Kanchan and Knowles, Tuomas P.J.}},
issn = {{0002-7863}},
language = {{eng}},
pages = {{16621--16629}},
publisher = {{The American Chemical Society (ACS)}},
series = {{Journal of the American Chemical Society}},
title = {{Mechanism of Secondary Nucleation at the Single Fibril Level from Direct Observations of Aβ42 Aggregation}},
url = {{http://dx.doi.org/10.1021/jacs.1c07228}},
doi = {{10.1021/jacs.1c07228}},
volume = {{143}},
year = {{2021}},
}