Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 143, Issue 40, Pages 16621-16629Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.1c07228
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Funding
- Herchel Smith Fund
- Department of Atomic Energy, Government of India [RTI 4007]
- Science and Engineering Research Board, Government of India [CRG/2020/005527]
- Swedish Research Council [2015-00143]
- European Research Council [337969]
- Frances and Augustus Newman Foundation
- Swedish Research Council [2015-00143] Funding Source: Swedish Research Council
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Understanding the mechanisms of amyloid formation and replication is crucial for studying neurodegenerative disorders like Alzheimer's disease. Secondary nucleation, which involves attachment of soluble species to fibril surfaces leading to the formation of new fibrils in solution, plays a key role in aggregate self-replication. This detailed insight into the process is essential for designing potential inhibitors of amyloid formation.
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 A beta 42 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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