Self-replication of Aβ42 aggregates occurs on small and isolated fibril sites

Samo Curk, Johannes Krausser, Georg Meisl, Daan Frenkel, Sara Linse, Thomas C.T. Michaels, Tuomas P.J. Knowles, Anđela Šarić

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)e2220075121
JournalProceedings of the National Academy of Sciences of the United States of America
Volume121
Issue number7
DOIs
Publication statusPublished - 2024 Feb 13

Subject classification (UKÄ)

  • Biophysics

Free keywords

  • amyloid aggregation
  • auto-catalysis
  • inhibition mechanism
  • secondary nucleation
  • self-replication

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