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A\u03b2 is generated by sequential proteolytic cleavage of amyloid precursor protein (APP), and the site of intracellular APP processing is highly debated, which may include autophagosomes. Here, we investigated the involvement of autophagy, including the role of ATG9 in APP intracellular trafficking and processing by applying the RUSH system, which allows studying the transport of fluorescently labeled mCherry\u2010APP\u2010EGFP in a systematic way, starting from the endoplasmic reticulum. HeLa cells, expressing the RUSH mCherry\u2010APP\u2010EGFP system, were investigated by live cell imaging, immunofluorescence, and Western blot. We found that mCherry\u2010APP\u2010EGFP passed through the Golgi faster in ATG9 knockout cells. Furthermore, ATG9 deletion shifted mCherry\u2010APP\u2010EGFP from early endosomes and lysosomes toward the plasma membrane concomitant with reduced endocytosis. Importantly, this alteration in mCherry\u2010APP\u2010EGFP transport resulted in increased secreted mCherry\u2010soluble APP and C\u2010terminal fragment\u2010EGFP. These effects were also phenocopied by pharmacological inhibition of ULK1, indicating that autophagy is regulating the intracellular trafficking and processing of APP. These findings contribute to the understanding of the role of autophagy in APP metabolism and could potentially have implications for new therapeutic approaches for AD.<\/jats:p>","DOI":"10.1111\/tra.12934","type":"journal-article","created":{"date-parts":[[2024,4,13]],"date-time":"2024-04-13T06:00:43Z","timestamp":1712988043000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Inhibition of Autophagy Alters Intracellular Transport of\u00a0\n                    <scp>APP<\/scp>\n                    Resulting in Increased\n                    <scp>APP<\/scp>\n                    Processing"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8921-5064","authenticated-orcid":false,"given":"Johanna","family":"Mayer","sequence":"first","affiliation":[{"name":"Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics Karolinska Institutet  Solna 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