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

Research output: Contribution to journalArticle

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.

Details

Authors
  • 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
  • Minkoo Ahn
  • Samuel T. Casford
  • Nilumi Fernando
  • Catherine K. Xu
  • Nina D. Kloss
  • Samuel I.A. Cohen
  • Janet R. Kumita
  • Cristina Cecchi
  • Michael Zasloff
  • Tuomas P.J. Knowles
  • Fabrizio Chiti
  • Michele Vendruscolo
  • Christopher M. Dobson
Organisations
External organisations
  • University of Cambridge
  • University of Florence
  • Harvard University
  • Georgetown University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medicinal Chemistry
  • Cell and Molecular Biology
Original languageEnglish
Article number225
JournalNature Communications
Volume10
Issue number1
Publication statusPublished - 2019 Dec 1
Publication categoryResearch
Peer-reviewedYes