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

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dc.contributor.authorJanuario, 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-Januario, Mara E.
dc.contributor.authorApolloni, Vinicius B.
dc.contributor.authorWilby, Elise L.
dc.contributor.authorAltmeyer, Randolf
dc.contributor.authorBurgos, Patricia, V
dc.contributor.authorCorrea, Sonia A. L.
dc.contributor.authorGershlick, David C.
dc.contributor.authordaSilva, Luis L. P.
dc.date.accessioned2025-01-20T21:02:39Z
dc.date.available2025-01-20T21:02:39Z
dc.date.issued2022
dc.description.abstractOne of the hallmarks of Alzheimer's disease is the accumulation of toxic amyloid-beta (A beta) peptides in extracellular plaques. The direct precursor of A beta is the carboxyl-terminal fragment beta (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 A beta. 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 A beta release. Our results indicate that AP-1 regulates the subcellular distribution of APP, altering its processing into neurotoxic fragments.
dc.fuente.origenWOS
dc.identifier.doi10.1016/j.jbc.2022.102172
dc.identifier.eissn1083-351X
dc.identifier.urihttps://doi.org/10.1016/j.jbc.2022.102172
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/93066
dc.identifier.wosidWOS:000848198300001
dc.issue.numero8
dc.language.isoen
dc.revistaJournal of biological chemistry
dc.rightsacceso restringido
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleClathrin adaptor AP-1-mediated Golgi export of amyloid precursor protein is crucial for the production of neurotoxic amyloid fragments
dc.typeartículo
dc.volumen298
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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