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Clathrin adaptor AP-1-mediated Golgi export of amyloid precursor protein is crucial for the production of neurotoxic amyloid fragments.

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cam.depositDate2022-07-01
cam.issuedOnline2022-06-23
cam.orpheus.success2022-07-01 - Embargo set during processing via Fast-track
dc.contributor.authorJanuário, Yunan C
dc.contributor.authorEden, Jessica
dc.contributor.authorde Oliveira, Luan S
dc.contributor.authorDe Pace, Raffaella
dc.contributor.authorTavares, Lucas A
dc.contributor.authorda Silva-Januário, Mara E
dc.contributor.authorApolloni, Vinícius B
dc.contributor.authorWilby, Elise L
dc.contributor.authorAltmeyer, Randolf
dc.contributor.authorBurgos, Patricia V
dc.contributor.authorCorrêa, Sonia AL
dc.contributor.authorGershlick, David C
dc.contributor.authordaSilva, Luis LP
dc.contributor.orcidAltmeyer, Randolf [0000-0003-2762-0093]
dc.contributor.orcidGershlick, David [0000-0002-0602-210X]
dc.date.accessioned2022-07-01T23:31:11Z
dc.date.available2022-07-01T23:31:11Z
dc.date.issued2022-08
dc.date.updated2022-07-01T14:42:33Z
dc.description.abstractOne of the hallmarks of Alzheimer's disease is the accumulation of toxic amyloid-β (Aβ) peptides in extracellular plaques. The direct precursor of Aβ is the carboxyl-terminal fragment β (or C99) of the amyloid precursor protein (APP). C99 is detected at elevated levels in Alzheimer's disease brains, and its intracellular accumulation has been linked to early neurotoxicity independently of Aβ. Despite this, the causes of increased C99 levels are poorly understood. Here, we demonstrate that APP interacts with the clathrin vesicle adaptor AP-1 (adaptor protein 1), and we map the interaction sites on both proteins. Using quantitative kinetic trafficking assays, established cell lines and primary neurons, we also show that this interaction is required for the transport of APP from the trans-Golgi network to endosomes. In addition, disrupting AP-1-mediated transport of APP alters APP processing and degradation, ultimately leading to increased C99 production and Aβ release. Our results indicate that AP-1 regulates the subcellular distribution of APP, altering its processing into neurotoxic fragments.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.86102
dc.identifier.eissn1083-351X
dc.identifier.issn0021-9258
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338689
dc.language.isoeng
dc.publisherElsevier BV
dc.publisher.departmentDepartment of Pure Mathematics And Mathematical Statistics
dc.publisher.departmentC.I.M.R. Clinical Biochemistry
dc.publisher.urlhttp://dx.doi.org/10.1016/j.jbc.2022.102172
dc.rightsAttribution 4.0 International (CC BY)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAlzheimer’s disease
dc.subjectadaptor protein 1
dc.subjectamyloid precursor protein
dc.subjectendosome
dc.subjectprotein trafficking (Golgi)
dc.subjectAdaptor Proteins, Vesicular Transport
dc.subjectAlzheimer Disease
dc.subjectAmyloid Precursor Protein Secretases
dc.subjectAmyloid beta-Peptides
dc.subjectAmyloid beta-Protein Precursor
dc.subjectAmyloidosis
dc.subjectGolgi Apparatus
dc.subjectHumans
dc.subjectNeurotoxicity Syndromes
dc.subjectTranscription Factor AP-1
dc.titleClathrin adaptor AP-1-mediated Golgi export of amyloid precursor protein is crucial for the production of neurotoxic amyloid fragments.
dc.typeArticle
dcterms.dateAccepted2022-06-09
prism.number102172
prism.publicationDate2022
prism.publicationNameJ Biol Chem
prism.startingPage102172
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/M011194/1)
pubs.funder-project-idWellcome Trust (210481/Z/18/Z)
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
pubs.licence-identifierapollo-deposit-licence-2-1
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1016/j.jbc.2022.102172

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