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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.date.accessioned2020-03-18T15:30:01Z
dc.date.available2020-03-18T15:30:01Z
dc.date.issued2019-04-04
dc.identifier266942418
dc.identifier76978a2e-ea16-4d47-8de4-4ae2386ebc63
dc.identifier30948723
dc.identifier85063980247
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 . https://doi.org/10.1038/s41467-019-09477-3en
dc.identifier.issn2041-1723
dc.identifier.otherPubMedCentral: PMC6449370
dc.identifier.otherORCID: /0000-0003-1901-1378/work/70920128
dc.identifier.urihttps://hdl.handle.net/10023/19675
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.format.extent11
dc.format.extent2736052
dc.language.isoeng
dc.relation.ispartofNature Communicationsen
dc.subjectIntrinsically disordered proteinsen
dc.subjectNanoscale biophysicsen
dc.subjectProtein aggregationen
dc.subjectSingle-molecule biophysicsen
dc.subjectQH301 Biologyen
dc.subjectRC0321 Neuroscience. Biological psychiatry. Neuropsychiatryen
dc.subjectDASen
dc.subject.lccQH301en
dc.subject.lccRC0321en
dc.titleDifferent soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanismsen
dc.typeJournal articleen
dc.contributor.institutionUniversity of St Andrews. School of Biologyen
dc.contributor.institutionUniversity of St Andrews. Centre for Biophotonicsen
dc.identifier.doi10.1038/s41467-019-09477-3
dc.description.statusPeer revieweden


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