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Trodusquemine enhances Aβ42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes

Author

Listed:
  • Ryan Limbocker

    (University of Cambridge)

  • Sean Chia

    (University of Cambridge)

  • Francesco S. Ruggeri

    (University of Cambridge)

  • Michele Perni

    (University of Cambridge)

  • Roberta Cascella

    (University of Florence)

  • Gabriella T. Heller

    (University of Cambridge)

  • Georg Meisl

    (University of Cambridge)

  • Benedetta Mannini

    (University of Cambridge)

  • Johnny Habchi

    (University of Cambridge)

  • Thomas C. T. Michaels

    (University of Cambridge
    Harvard University)

  • Pavan K. Challa

    (University of Cambridge)

  • Minkoo Ahn

    (University of Cambridge)

  • Samuel T. Casford

    (University of Cambridge)

  • Nilumi Fernando

    (University of Cambridge)

  • Catherine K. Xu

    (University of Cambridge)

  • Nina D. Kloss

    (University of Cambridge)

  • Samuel I. A. Cohen

    (University of Cambridge)

  • Janet R. Kumita

    (University of Cambridge)

  • Cristina Cecchi

    (University of Florence)

  • Michael Zasloff

    (Georgetown University School of Medicine)

  • Sara Linse

    (Lund University)

  • Tuomas P. J. Knowles

    (University of Cambridge
    University of Cambridge)

  • Fabrizio Chiti

    (University of Florence)

  • Michele Vendruscolo

    (University of Cambridge)

  • Christopher M. Dobson

    (University of Cambridge)

Abstract

Transient oligomeric species formed during the aggregation process of the 42-residue form of the amyloid-β peptide (Aβ42) are key pathogenic agents in Alzheimer’s disease (AD). To investigate the relationship between Aβ42 aggregation and its cytotoxicity and the influence of a potential drug on both phenomena, we have studied the effects of trodusquemine. This aminosterol enhances the rate of aggregation by promoting monomer-dependent secondary nucleation, but significantly reduces the toxicity of the resulting oligomers to neuroblastoma cells by inhibiting their binding to the cellular membranes. When administered to a C. elegans model of AD, we again observe an increase in aggregate formation alongside the suppression of Aβ42-induced toxicity. In addition to oligomer displacement, the reduced toxicity could also point towards an increased rate of conversion of oligomers to less toxic fibrils. The ability of a small molecule to reduce the toxicity of oligomeric species represents a potential therapeutic strategy against AD.

Suggested Citation

  • Ryan Limbocker & Sean Chia & Francesco S. Ruggeri & Michele Perni & Roberta Cascella & Gabriella T. Heller & Georg Meisl & Benedetta Mannini & Johnny Habchi & Thomas C. T. Michaels & Pavan K. Challa &, 2019. "Trodusquemine enhances Aβ42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-07699-5
    DOI: 10.1038/s41467-018-07699-5
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    Cited by:

    1. Yong Xu & Roberto Maya-Martinez & Nicolas Guthertz & George R. Heath & Iain W. Manfield & Alexander L. Breeze & Frank Sobott & Richard Foster & Sheena E. Radford, 2022. "Tuning the rate of aggregation of hIAPP into amyloid using small-molecule modulators of assembly," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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