Novel mechanistic insight into the molecular basis of amyloid polymorphism and secondary nucleation during amyloid formation

Jae Sun Jeong, Annalisa Ansaloni, Raffaele Mezzenga, Hilal A. Lashuel, Giovanni Dietler

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

The formation of amyloid β (Aβ) fibrils is crucial in initiating the cascade of pathological events that culminates in Alzheimer's disease. In this study, we investigated the mechanism of Aβ fibril formation from hydrodynamically well defined species under controlled aggregation conditions. We present a detailed mechanistic model that furnishes a novel insight into the process of Aβ42 fibril formation and the molecular basis for the different structural transitions in the amyloid pathway. Our data reveal the structure and polymorphism of Aβ fibrils to be critically influenced by the oligomeric state of the starting materials, the ratio of monomeric-to-aggregated forms of Aβ42 (oligomers and protofibrils), and the occurrence of secondary nucleation. We demonstrate that monomeric Aβ42 plays an important role in mediating structural transitions in the amyloid pathway, and for the first time, we provide evidences that Aβ42 fibrillization occurs via a combined mechanism of nucleated polymerization and secondary nucleation. These findings will have significant implications to our understanding of the molecular basis of amyloid formation in vivo, of the heterogeneity of Aβ pathology (e.g.; diffuse versus amyloid plaques), and of the structural basis of Aβ toxicity.

Original languageEnglish
Pages (from-to)1765-1781
Number of pages17
JournalJournal of Molecular Biology
Volume425
Issue number10
DOIs
Publication statusPublished - 27 May 2013
Externally publishedYes

Fingerprint

Amyloid
Amyloid Plaques
Polymerization
Alzheimer Disease
Pathology

Keywords

  • Aβ42
  • amyloid
  • atomic force microscopy
  • mechanism
  • nucleation

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Novel mechanistic insight into the molecular basis of amyloid polymorphism and secondary nucleation during amyloid formation. / Jeong, Jae Sun; Ansaloni, Annalisa; Mezzenga, Raffaele; Lashuel, Hilal A.; Dietler, Giovanni.

In: Journal of Molecular Biology, Vol. 425, No. 10, 27.05.2013, p. 1765-1781.

Research output: Contribution to journalArticle

Jeong, Jae Sun ; Ansaloni, Annalisa ; Mezzenga, Raffaele ; Lashuel, Hilal A. ; Dietler, Giovanni. / Novel mechanistic insight into the molecular basis of amyloid polymorphism and secondary nucleation during amyloid formation. In: Journal of Molecular Biology. 2013 ; Vol. 425, No. 10. pp. 1765-1781.
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