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

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 ZasloffSara Linse, Tuomas P.J. Knowles, Fabrizio Chiti, Michele Vendruscolo, Christopher M. Dobson

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

77 Citeringar (SciVal)

Sammanfattning

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.

Originalspråkengelska
Artikelnummer225
TidskriftNature Communications
Volym10
Nummer1
DOI
StatusPublished - 2019 dec. 1

Ämnesklassifikation (UKÄ)

  • Läkemedelskemi
  • Cell- och molekylärbiologi

Fingeravtryck

Utforska forskningsämnen för ”Trodusquemine enhances Aβ42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes”. Tillsammans bildar de ett unikt fingeravtryck.

Citera det här