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- Title
Trodusquemine enhances Aβ<sub>42</sub> aggregation but suppresses its toxicity by displacing oligomers from cell membranes.
- Authors
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
- 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. Transient oligomeric species of the amyloid-β peptide (Aβ42) have been identified as key pathogenic agents in Alzheimer's disease. Here the authors find that the aminosterol trodusquemine enhances Aβ42 aggregation and suppresses Aβ42-induced toxicity by displacing oligomers from cell membranes.
- Publication
Nature Communications, 2019, Vol 10, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-07699-5