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

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.

SUBMITTER: Limbocker R 

PROVIDER: S-EPMC6333784 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature