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Intracellular Aβ42 Aggregation Leads to Cellular Thermogenesis.

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cam.issuedOnline2022-05-26
datacite.issupplementedby.urlhttps://doi.org/10.17863/CAM.82938
dc.contributor.authorChung, Chyi Wei
dc.contributor.authorStephens, Amberley D
dc.contributor.authorKonno, Tasuku
dc.contributor.authorWard, Edward
dc.contributor.authorAvezov, Edward
dc.contributor.authorKaminski, Clemens F
dc.contributor.authorHassanali, Ali A
dc.contributor.authorKaminski Schierle, Gabriele S
dc.contributor.orcidChung, Chyi Wei [0000-0003-1780-3486]
dc.contributor.orcidStephens, Amberley D [0000-0002-7303-6392]
dc.contributor.orcidKaminski, Clemens F [0000-0002-5194-0962]
dc.contributor.orcidHassanali, Ali A [0000-0002-3208-1488]
dc.contributor.orcidKaminski Schierle, Gabriele S [0000-0002-1843-2202]
dc.date.accessioned2022-06-29T19:47:21Z
dc.date.available2022-06-29T19:47:21Z
dc.date.issued2022-06-08
dc.date.updated2022-06-29T19:47:20Z
dc.descriptionFunder: Cambridge Commonwealth, European and International Trust
dc.descriptionFunder: Infinitus China Ltd.
dc.description.abstractThe aggregation of Aβ42 is a hallmark of Alzheimer's disease. It is still not known what the biochemical changes are inside a cell which will eventually lead to Aβ42 aggregation. Thermogenesis has been associated with cellular stress, the latter of which may promote aggregation. We perform intracellular thermometry measurements using fluorescent polymeric thermometers to show that Aβ42 aggregation in live cells leads to an increase in cell-averaged temperatures. This rise in temperature is mitigated upon treatment with an aggregation inhibitor of Aβ42 and is independent of mitochondrial damage that can otherwise lead to thermogenesis. With this, we present a diagnostic assay which could be used to screen small-molecule inhibitors to amyloid proteins in physiologically relevant settings. To interpret our experimental observations and motivate the development of future models, we perform classical molecular dynamics of model Aβ peptides to examine the factors that hinder thermal dissipation. We observe that this is controlled by the presence of ions in its surrounding environment, the morphology of the amyloid peptides, and the extent of its hydrogen-bonding interactions with water. We show that aggregation and heat retention by Aβ peptides are favored under intracellular-mimicking ionic conditions, which could potentially promote thermogenesis. The latter will, in turn, trigger further nucleation events that accelerate disease progression.
dc.identifier.doi10.17863/CAM.85952
dc.identifier.eissn1520-5126
dc.identifier.issn0002-7863
dc.identifier.other35616634
dc.identifier.otherPMC9185738
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338539
dc.languageeng
dc.language.isoeng
dc.publisherAmerican Chemical Society (ACS)
dc.publisher.urlhttp://dx.doi.org/10.1021/jacs.2c03599
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 1520-5126
dc.sourcenlmid: 7503056
dc.subjectAlzheimer Disease
dc.subjectAmyloid beta-Peptides
dc.subjectHumans
dc.subjectPeptide Fragments
dc.subjectThermogenesis
dc.titleIntracellular Aβ42 Aggregation Leads to Cellular Thermogenesis.
dc.typeArticle
prism.endingPage10041
prism.issueIdentifier22
prism.publicationNameJ Am Chem Soc
prism.startingPage10034
prism.volume144
pubs.funder-project-idMedical Research Council (MR/K02292X/1)
pubs.funder-project-idWellcome Trust (065807/Z/01/Z)
pubs.funder-project-idWellcome Trust (203249/Z/16/Z)
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1021/jacs.2c03599

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