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

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cam.issuedOnline2019-01-15
dc.contributor.authorLimbocker, Ryan
dc.contributor.authorChia, Sean
dc.contributor.authorRuggeri, Francesco S
dc.contributor.authorPerni, Michele
dc.contributor.authorCascella, Roberta
dc.contributor.authorHeller, Gabriella T
dc.contributor.authorMeisl, Georg
dc.contributor.authorMannini, Benedetta
dc.contributor.authorHabchi, Johnny
dc.contributor.authorMichaels, Thomas CT
dc.contributor.authorChalla, Pavan K
dc.contributor.authorAhn, Minkoo
dc.contributor.authorCasford, Samuel T
dc.contributor.authorFernando, Nilumi
dc.contributor.authorXu, Catherine K
dc.contributor.authorKloss, Nina D
dc.contributor.authorCohen, Samuel IA
dc.contributor.authorKumita, Janet R
dc.contributor.authorCecchi, Cristina
dc.contributor.authorZasloff, Michael
dc.contributor.authorLinse, Sara
dc.contributor.authorKnowles, Tuomas PJ
dc.contributor.authorChiti, Fabrizio
dc.contributor.authorVendruscolo, Michele
dc.contributor.authorDobson, Christopher M
dc.contributor.orcidPerni, Michele [0000-0001-7593-8376]
dc.contributor.orcidMeisl, Georg [0000-0002-6562-7715]
dc.contributor.orcidMannini, Benedetta [0000-0001-6812-7348]
dc.contributor.orcidAhn, Minkoo [0000-0001-9131-7334]
dc.contributor.orcidKumita, Janet R [0000-0002-3887-4964]
dc.contributor.orcidLinse, Sara [0000-0001-9629-7109]
dc.contributor.orcidChiti, Fabrizio [0000-0002-1330-1289]
dc.contributor.orcidDobson, Christopher M [0000-0002-3616-1610]
dc.date.accessioned2019-01-18T00:30:43Z
dc.date.available2019-01-18T00:30:43Z
dc.date.issued2019-01-15
dc.description.abstractTransient 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.
dc.description.sponsorshipThis 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).
dc.format.mediumElectronic
dc.identifier.doi10.17863/CAM.35469
dc.identifier.eissn2041-1723
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/288153
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/s41467-018-07699-5
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAlzheimer Disease
dc.subjectAmyloid beta-Peptides
dc.subjectAnimals
dc.subjectCaenorhabditis elegans
dc.subjectCell Line, Tumor
dc.subjectCholestanes
dc.subjectDrug Evaluation, Preclinical
dc.subjectPeptide Fragments
dc.subjectSpermine
dc.titleTrodusquemine enhances Aβ42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes.
dc.typeArticle
dcterms.dateAccepted2018-11-05
prism.issueIdentifier1
prism.publicationDate2019
prism.publicationNameNat Commun
prism.startingPage225
prism.volume10
pubs.funder-project-idWellcome Trust (094425/Z/10/Z)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/J002119/1)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/K039520/1)
rioxxterms.licenseref.startdate2019-01-15
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41467-018-07699-5

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