Self-replication of Aβ₄₂ aggregates occurs on small and isolated fibril sites
Abstract
Self-replication of amyloid fibrils via secondary nucleation is an intriguing physicochemical phenomenon in which existing fibrils catalyze the formation of their own copies. The molecular events behind this fibril surface-mediated process remain largely inaccessible to current structural and imaging techniques. Using statistical mechanics, computer modeling, and chemical kinetics, we show that the catalytic structure of the fibril surface can be inferred from the aggregation behavior in the presence and absence of a fibril-binding inhibitor. We apply our approach to the case of Alzheimer's A[Formula: see text] amyloid fibrils formed in the presence of proSP-C Brichos inhibitors. We find that self-replication of A[Formula: see text] fibrils occurs on small catalytic sites on the fibril surface, which are far apart from each other, and each of which can be covered by a single Brichos inhibitor. Show more
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https://doi.org/10.3929/ethz-b-000660116Publication status
publishedExternal links
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Proceedings of the National Academy of Sciences of the United States of AmericaVolume
Pages / Article No.
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National Academy of SciencesSubject
self-replication; amyloid aggregation; auto-catalysis; secondary nucleation; inhibition mechanismRelated publications and datasets
Is new version of: https://doi.org/10.3929/ethz-b-000655336
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