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dc.contributor.authorColeman, Michaelen
dc.contributor.authorDurrant, Claire Sen
dc.contributor.authorRuscher, Karstenen
dc.contributor.authorSheppard, Oliviaen
dc.contributor.authorÖzen, Ilknuren
dc.date.accessioned2020-02-08T00:30:35Z
dc.date.available2020-02-08T00:30:35Z
dc.identifier.issn2041-4889
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/301847
dc.description.abstractAmyloid beta peptides (Aβ) proteins play a key role in vascular pathology in Alzheimer’s Disease (AD) including impairment of the blood brain barrier and aberrant angiogenesis. Although previous work has demonstrated a pro-angiogenic role of Aβ, the exact mechanisms by which amyloid precursor protein (APP) processing and endothelial angiogenic signalling cascades interact in AD remain a largely unsolved problem. Here, we report that increased endothelial sprouting in human-APP transgenic mouse (TgCRND8) tissue is dependent on β-secretase (BACE1) processing of APP. Higher levels of Aβ processing in TgCRND8 tissue coincides with decreased NOTCH3/JAG1 signalling, over-production of endothelial filopodia and increased numbers of vascular pericytes. Using a novel in vitro approach to study sprouting angiogenesis in TgCRND8 organotypic brain slice cultures (OBSCs), we find that BACE1 inhibition normalises excessive endothelial filopodia formation and restores NOTCH3 signalling. These data present the first evidence for the potential of BACE1 inhibition as an effective therapeutic target for aberrant angiogenesis in AD.
dc.description.sponsorshipThis work was funded by Alzheimer's Research UK project grant ARUK-PG2015-24, the John and Lucille Van Geest Foundation, Swedish Brain Fund (FO2019-0254; FO218-0316), the Hans-Gabriel and Alice Trolle-Wachtmeister Foundation and Sparbanksstiftelsen Fars & Frosta.
dc.publisherNature Publishing Group
dc.rightsAttribution 4.0 International (CC BY)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleBeta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signalingen
dc.typeArticle
prism.number98en
prism.publicationNameCell Death and Diseaseen
prism.volume11en
dc.identifier.doi10.17863/CAM.48915
dcterms.dateAccepted2020-01-22en
rioxxterms.versionofrecord10.1038/s41419-020-2288-4en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2020-01-22en
dc.contributor.orcidColeman, Michael [0000-0002-9354-532X]
dc.contributor.orcidSheppard, Olivia [0000-0001-5636-3925]
dc.identifier.eissn2041-4889
rioxxterms.typeJournal Article/Reviewen
cam.issuedOnline2020-02-06en
cam.orpheus.successTue Mar 31 10:37:16 BST 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International (CC BY)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY)