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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • 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
Enheter & grupper
Externa organisationer
  • University of Cambridge
  • University of Florence
  • Harvard University
  • Georgetown University
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Läkemedelskemi
  • Cell- och molekylärbiologi
Originalspråkengelska
Artikelnummer225
TidskriftNature Communications
Volym10
Utgivningsnummer1
StatusPublished - 2019 dec 1
PublikationskategoriForskning
Peer review utfördJa