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 Zasloff, Sara Linse, Tuomas P. J. Knowles, Fabrizio Chiti (), Michele Vendruscolo () and Christopher M. Dobson ()
Additional contact information
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
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
Fabrizio Chiti: University of Florence
Michele Vendruscolo: University of Cambridge
Christopher M. Dobson: University of Cambridge

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-07699-5

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