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dc.contributor.authorAnderson, Emma L.
dc.contributor.authorWilliams, Dylan M.
dc.contributor.authorWalker, Venexia M.
dc.contributor.authorDavies, Neil Martin
dc.date.accessioned2023-03-06T12:09:30Z
dc.date.available2023-03-06T12:09:30Z
dc.date.created2022-05-02T10:52:14Z
dc.date.issued2022
dc.identifier.citationScientific Reports. 2022, 12 (1), .en_US
dc.identifier.issn2045-2322
dc.identifier.urihttps://hdl.handle.net/11250/3056029
dc.description.abstractTherapeutic targets for halting the progression of Alzheimer’s disease pathology are lacking. Recent evidence suggests that APOE4, but not APOE3, activates the Cyclophilin-A matrix metalloproteinase-9 (CypA-MMP9) pathway, leading to an accelerated breakdown of the blood–brain barrier (BBB) and thereby causing neuronal and synaptic dysfunction. Furthermore, blockade of the CypA-MMP9 pathway in APOE4 knock-in mice restores BBB integrity and subsequently normalizes neuronal and synaptic function. Thus, CypA has been suggested as a potential target for treating APOE4 mediated neurovascular injury and the resulting neuronal dysfunction and degeneration. The odds of drug targets passing through clinical trials are greatly increased if they are supported by genomic evidence. We found little evidence to suggest that CypA or MMP9 affects the risk of Alzheimer’s disease or cognitive impairment using two-sample Mendelian randomization and polygenic risk score analysis in humans. This casts doubt on whether they are likely to represent effective drug targets for cognitive impairment in human APOE4 carriers.en_US
dc.language.isoengen_US
dc.publisherSpringer Natureen_US
dc.rightsNavngivelse 4.0 Internasjonal*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/deed.no*
dc.titleLittle genomic support for Cyclophilin A-matrix metalloproteinase-9 pathway as a therapeutic target for cognitive impairment in APOE4 carriersen_US
dc.title.alternativeLittle genomic support for Cyclophilin A-matrix metalloproteinase-9 pathway as a therapeutic target for cognitive impairment in APOE4 carriersen_US
dc.typePeer revieweden_US
dc.typeJournal articleen_US
dc.description.versionpublishedVersionen_US
dc.source.volume12en_US
dc.source.journalScientific Reportsen_US
dc.identifier.doi10.1038/s41598-022-05225-8
dc.identifier.cristin2020536
dc.relation.projectNorges forskningsråd: 295989en_US
dc.source.articlenumber1057en_US
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode1


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