Nature communications · 2019
Trodusquemine enhances Aβ42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes.
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Limbocker Ryan, Chia Sean, Ruggeri Francesco S, Perni Michele, Cascella Roberta, Heller Gabriella T, Meisl Georg, Mannini Benedetta, Habchi Johnny, Michaels Thomas C T, Challa Pavan K, Ahn Minkoo, Casford Samuel T, Fernando Nilumi, Xu Catherine K, Kloss Nina D, Cohen Samuel I A, Kumita Janet R, Cecchi Cristina, Zasloff Michael, Linse Sara, Knowles Tuomas P J, Chiti Fabrizio, Vendruscolo Michele, Dobson Christopher M
Аннотация
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.