Advanced

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

Limbocker, Ryan; Chia, Sean; Ruggeri, Francesco S.; Perni, Michele; Cascella, Roberta; Heller, Gabriella T.; Meisl, Georg; Mannini, Benedetta; Habchi, Johnny and Michaels, Thomas C.T., et al. (2019) In Nature Communications 10(1).
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
@article{feaa2c3c-33e4-40d3-bfb2-e6edaa2233b1,
  abstract     = {<p>Transient oligomeric species formed during the aggregation process of the 42-residue form of the amyloid-β peptide (Aβ<sub>42</sub>) are key pathogenic agents in Alzheimer’s disease (AD). To investigate the relationship between Aβ<sub>42</sub> 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 Aβ<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.</p>},
  articleno    = {225},
  author       = {Limbocker, Ryan and Chia, Sean and Ruggeri, Francesco S. and Perni, Michele and Cascella, Roberta and Heller, Gabriella T. and Meisl, Georg and Mannini, Benedetta and Habchi, Johnny and Michaels, Thomas C.T. and Challa, Pavan K. and Ahn, Minkoo and Casford, Samuel T. and Fernando, Nilumi and Xu, Catherine K. and Kloss, Nina D. and Cohen, Samuel I.A. and Kumita, Janet R. and Cecchi, Cristina and Zasloff, Michael and Linse, Sara and Knowles, Tuomas P.J. and Chiti, Fabrizio and Vendruscolo, Michele and Dobson, Christopher M.},
  issn         = {2041-1723},
  language     = {eng},
  month        = {12},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Trodusquemine enhances Aβ<sub>42</sub> aggregation but suppresses its toxicity by displacing oligomers from cell membranes},
  url          = {http://dx.doi.org/10.1038/s41467-018-07699-5},
  volume       = {10},
  year         = {2019},
}