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dc.contributor.authorHung, Christyen
dc.contributor.authorLivesey, Fredericken
dc.date.accessioned2019-01-08T00:31:28Z
dc.date.available2019-01-08T00:31:28Z
dc.date.issued2018-12en
dc.identifier.issn2211-1247
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/287623
dc.description.abstractAbnormalities of the endolysosomal and autophagy systems are found in Alzheimer’s disease, but it is not clear whether defects in these systems are a cause or consequence of degenerative processes in the disease. In human neuronal models of monogenic Alzheimer’s disease, APP and PSEN1 mutations disrupt lysosome function and autophagy, leading to impaired lysosomal proteolysis and defective autophagosome clearance. Processing of APP by γ-secretase is central to the pathogenic changes in the lysosome-autophagy system caused by PSEN1 and APP mutations: reducing production of C-terminal APP by inhibition of BACE1 rescued these phenotypes in both APP and PSEN1 mutant neurons, whereas inhibition of γ-secretase induced lysosomal and autophagic pathology in healthy neurons. Defects in lysosomes and autophagy due to PSEN1 mutations are rescued by CRISPR-knockout of APP. These data demonstrate a key role for proteolysis of the C-terminal of APP by γ-secretase in neuronal dysfunction in monogenic Alzheimer’s disease.
dc.format.mediumPrinten
dc.languageengen
dc.publisherElsevier
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCerebral Cortexen
dc.subjectAxonsen
dc.subjectEndosomesen
dc.subjectLysosomesen
dc.subjectHumansen
dc.subjectAlzheimer Diseaseen
dc.subjectAmyloid beta-Protein Precursoren
dc.subjectProtein Processing, Post-Translationalen
dc.subjectMutationen
dc.subjectAutophagyen
dc.subjectAmyloid Precursor Protein Secretasesen
dc.subjectPresenilin-1en
dc.subjectProteolysisen
dc.subjectCRISPR-Cas Systemsen
dc.subjectAutophagosomesen
dc.titleAltered γ-Secretase Processing of APP Disrupts Lysosome and Autophagosome Function in Monogenic Alzheimer's Disease.en
dc.typeArticle
prism.endingPage3660.e2
prism.issueIdentifier13en
prism.publicationDate2018en
prism.publicationNameCell reportsen
prism.startingPage3647
prism.volume25en
dc.identifier.doi10.17863/CAM.34935
dcterms.dateAccepted2018-11-27en
rioxxterms.versionofrecord10.1016/j.celrep.2018.11.095en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-12en
dc.contributor.orcidHung, Christy [0000-0002-6063-8263]
dc.contributor.orcidLivesey, Frederick [0000-0001-6128-3372]
dc.identifier.eissn2211-1247
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idAlzheimer's Research UK (ARUK-SCRC2014-1)
pubs.funder-project-idWELLCOME TRUST (101052/2/13/Z)


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