Details

Autor(en) / Beteiligte

• 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

Titel

Trodusquemine enhances Aβ 42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes

Ist Teil von

• Nature communications, 2019-12, Vol.10 (1), p.225

Ort / Verlag

England

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• Transient oligomeric species formed during the aggregation process of the 42-residue form of the amyloid-β peptide (Aβ ) are key pathogenic agents in Alzheimer's disease (AD). To investigate the relationship between Aβ 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 -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.