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

Authors
Limbocker, Ryan 
Chia, Sean 
Ruggeri, Francesco S 
Cascella, Roberta 

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Article
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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.

Publication Date
2019-01-15
Online Publication Date
2019-01-15
Acceptance Date
2018-11-05
Keywords
Alzheimer Disease, Amyloid beta-Peptides, Animals, Caenorhabditis elegans, Cell Line, Tumor, Cholestanes, Drug Evaluation, Preclinical, Peptide Fragments, Spermine
Journal Title
Nat Commun
Journal ISSN
2041-1723
2041-1723
Volume Title
10
Publisher
Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (094425/Z/10/Z)
Biotechnology and Biological Sciences Research Council (BB/J002119/1)
Engineering and Physical Sciences Research Council (EP/K039520/1)
This work was supported by the Cambridge Centre for Misfolding Diseases (R.L., S.C., F.S.R., M.P., G.T.H., G.M., B.M., J.H., T.C.T.M, P.K.C., M.A., S.T.C., N.F., C.K.X., N.D.K., J.R.K., T.P.J.K., M.V. and C.M.D.), the UK Biotechnology and Biochemical Sciences Research Council (M.V. and C.M.D.), the Wellcome Trust (T.P.J.K, M.V. and C.M.D.), the Frances and Augustus Newman Foundation (T.P.J.K.), the Regione Toscana – FAS Salute (R.C., C.C. and F.C.), Darwin College Cambridge (F.S.R.), Sidney Sussex College Cambridge (G.M.), Peterhouse College Cambridge (T.C.T.M), the Swiss National Science Foundation (T.C.T.M.), a Gates Cambridge Scholarship (R.L. and G.T.H.) and a St. John’s College Benefactors’ Scholarship (R.L.). The NMR facility (Department of Chemistry, University of Cambridge) is supported, in part, by an EPSRC Core Capability grant (EP/K039520/1).