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dc.contributor.authorDe, Suman
dc.contributor.authorWirthensohn, David C
dc.contributor.authorFlagmeier, Patrick
dc.contributor.authorHughes, Craig
dc.contributor.authorAprile, Francesco A
dc.contributor.authorRuggeri, Francesco S
dc.contributor.authorWhiten, Daniel R
dc.contributor.authorEmin, Derya
dc.contributor.authorXia, Zengjie
dc.contributor.authorVarela, Juan A
dc.contributor.authorSormanni, Pietro
dc.contributor.authorKundel, Franziska
dc.contributor.authorKnowles, Tuomas P J
dc.contributor.authorDobson, Christopher M
dc.contributor.authorBryant, Clare
dc.contributor.authorVendruscolo, Michele
dc.contributor.authorKlenerman, David
dc.identifier.citationDe , S , Wirthensohn , D C , Flagmeier , P , Hughes , C , Aprile , F A , Ruggeri , F S , Whiten , D R , Emin , D , Xia , Z , Varela , J A , Sormanni , P , Kundel , F , Knowles , T P J , Dobson , C M , Bryant , C , Vendruscolo , M & Klenerman , D 2019 , ' Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms ' , Nature Communications , vol. 10 , 1541 .
dc.identifier.otherPURE: 266942418
dc.identifier.otherPURE UUID: 76978a2e-ea16-4d47-8de4-4ae2386ebc63
dc.identifier.otherPubMed: 30948723
dc.identifier.otherPubMedCentral: PMC6449370
dc.identifier.otherScopus: 85063980247
dc.identifier.otherORCID: /0000-0003-1901-1378/work/70920128
dc.descriptionFunding: This study is supported by the Marie-Curie Individual Fellowship programme (to S.D.), EPSRC Studentship (to D.C.W.), Boehringer Ingelheim Fonds (to P.F.), Studienstiftung des deutschen Volkes (to P.F.), Senior Research Fellowship from the Alzheimer’s Society, Grant Number 317, AS-SF-16-003, UK (to F.A.A), Swiss National Fondation for Science and Darwin College grant number P2ELP2_162116 and P300P2_171219 (to F.S.R.), Borysiewicz Biomedical Fellowship from the University of Cambridge (to P.S), the UK Biotechnology and Biochemical Sciences Research Council (to C.M.D.); the Wellcome Trust (to C.M.D), the Cambridge Centre for Misfolding Diseases (to P.F., F.A.A., P.S.,C.M.D., and M.V.) and the European Research Council Grant Number 669237 (to D.K.) and the Royal Society (to D.K.).en
dc.description.abstractProtein aggregation is a complex process resulting in the formation of heterogeneous mixtures of aggregate populations that are closely linked to neurodegenerative conditions, such as Alzheimer's disease. Here, we find that soluble aggregates formed at different stages of the aggregation process of amyloid beta (Aβ42) induce the disruption of lipid bilayers and an inflammatory response to different extents. Further, by using gradient ultracentrifugation assay, we show that the smaller aggregates are those most potent at inducing membrane permeability and most effectively inhibited by antibodies binding to the C-terminal region of Aβ42. By contrast, we find that the larger soluble aggregates are those most effective at causing an inflammatory response in microglia cells and more effectively inhibited by antibodies targeting the N-terminal region of Aβ42. These findings suggest that different toxic mechanisms driven by different soluble aggregated species of Aβ42 may contribute to the onset and progression of Alzheimer's disease.
dc.relation.ispartofNature Communicationsen
dc.rightsCopyright © The Author(s) 2019. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
dc.subjectIntrinsically disordered proteinsen
dc.subjectNanoscale biophysicsen
dc.subjectProtein aggregationen
dc.subjectSingle-molecule biophysicsen
dc.subjectQH301 Biologyen
dc.subjectRC0321 Neuroscience. Biological psychiatry. Neuropsychiatryen
dc.titleDifferent soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanismsen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. School of Biologyen
dc.contributor.institutionUniversity of St Andrews. Centre for Biophotonicsen
dc.description.statusPeer revieweden

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