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Resources » Paper

Limbocker R et al. (2019) Nat Commun "Trodusquemine enhances A42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes."

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  • Comments on Limbocker R et al. (2019) Nat Commun "Trodusquemine enhances A42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes." (0)

  • Overview

    PMID:
    30644384
    DOI:
    10.1038/s41467-018-07699-5
    Status:
    Publication type:
    Journal_article
    WormBase ID:
    WBPaper00056043

    Limbocker R, Chia S, Ruggeri FS, Perni M, Cascella R, Heller GT, Meisl G, Mannini B, Habchi J, Michaels TCT, Challa PK, Ahn M, Casford ST, Fernando N, Xu CK, Kloss ND, Cohen SIA, Kumita JR, Cecchi C, Zasloff M, Linse S, Knowles TPJ, Chiti F, Vendruscolo M, & Dobson CM (2019). Trodusquemine enhances A42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes. Nat Commun, 10, 225. doi:10.1038/s41467-018-07699-5

    Transient oligomeric species formed during the aggregation process of the 42-residue form of the amyloid- peptide (A<sub>42</sub>) are key pathogenic agents in Alzheimer's disease (AD). To investigate the relationship between A<sub>42</sub> aggregation and its cytotoxicity and the influence of a potentialdrug 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 A<sub>42</sub>-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.

    Authors: Limbocker R, Chia S, Ruggeri FS, Perni M, Cascella R, Heller GT, Meisl G, Mannini B, Habchi J, Michaels TCT, Challa PK, Ahn M, Casford ST, Fernando N, Xu CK, Kloss ND, Cohen SIA, Kumita JR, Cecchi C, Zasloff M, Linse S, Knowles TPJ, Chiti F, Vendruscolo M, Dobson CM


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