Browsing by Author "Apolloni, Vinicius B."

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    Clathrin adaptor AP-1-mediated Golgi export of amyloid precursor protein is crucial for the production of neurotoxic amyloid fragments
    (2022) Januario, Yunan C.; Eden, Jessica; de Oliveira, Luan S.; De Pace, Raffaella; Tavares, Lucas A.; da Silva-Januario, Mara E.; Apolloni, Vinicius B.; Wilby, Elise L.; Altmeyer, Randolf; Burgos, Patricia, V; Correa, Sonia A. L.; Gershlick, David C.; daSilva, Luis L. P.
    One 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.