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

Nature communications (2019-01-16)
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, Christopher M Dobson
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.

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