{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T11:02:50Z","timestamp":1785322970746,"version":"3.55.0"},"reference-count":82,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Beaconbright Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a progressive neurodegenerative disorder characterized by the buildup of aggregated amyloid-beta (A\u03b2) peptides. We previously demonstrated that A\u03b2 is produced from APP following its lysosomal internalization via macropinocytosis. However, the regulation of APP macropinocytosis in neuronal cells remained uncharacterized. Arf6 and the Rho GTPases Rac1, Cdc42 and RhoA are known to regulate macropinocytosis in response to signaling at the cell surface. Fe65, an adaptor protein known to interact with APP, may link APP to these regulatory elements. We hypothesized that APP binding\/crosslinking recruits Fe65, which recruits\/activates Arf6 and then Rac1, Cdc42, and RhoA, driving APP macropinocytosis. We found that antibody-mediated binding\/crosslinking APP resulted in the transient recruitment of Fe65 and Arf6 to APP within 30 s of APP binding\/crosslinking. Rac1, Cdc42, and RhoA were also recruited at 30 s, but remained recruited through 2 min. The mutation of the APP \u2018YENPTY\u2019 sequence and Arf6 inhibition by NAV-2729 prevented the recruitment of Rac1, Cdc42, and RhoA. Together, these observations are the first to demonstrate that a network of regulatory proteins is recruited to bound\/crosslinked APP and regulates its macropinocytosis. Targeting these regulatory proteins to modulate APP trafficking to the lysosome could be a therapeutic strategy to reduce A\u03b2 production in AD.<\/jats:p>","DOI":"10.3390\/cells15151366","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T10:13:47Z","timestamp":1785320027000},"page":"1366","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Macropinocytosis of Amyloid Precursor Protein Is Regulated by the Recruitment and Activity of Fe65, Arf6 and Rho GTPases"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8042-3851","authenticated-orcid":false,"given":"Jordan M.","family":"Krupa","sequence":"first","affiliation":[{"name":"Neuroscience Program, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5B7, Canada"},{"name":"J. Allyn Taylor Centre for Cell Biology, Molecular Medicine Research Group, Robarts Research Institute, 1151 Richmond St, London, ON N6A 5B8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6342-5546","authenticated-orcid":false,"given":"Manoj Reddy","family":"Medapati","sequence":"additional","affiliation":[{"name":"J. Allyn Taylor Centre for Cell Biology, Molecular Medicine Research Group, Robarts Research Institute, 1151 Richmond St, London, ON N6A 5B8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul M.","family":"Naqvi","sequence":"additional","affiliation":[{"name":"Neuroscience Program, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5B7, Canada"},{"name":"J. Allyn Taylor Centre for Cell Biology, Molecular Medicine Research Group, Robarts Research Institute, 1151 Richmond St, London, ON N6A 5B8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan D.","family":"Hallam","sequence":"additional","affiliation":[{"name":"J. Allyn Taylor Centre for Cell Biology, Molecular Medicine Research Group, Robarts Research Institute, 1151 Richmond St, London, ON N6A 5B8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrianna R.","family":"Tsang","sequence":"additional","affiliation":[{"name":"J. Allyn Taylor Centre for Cell Biology, Molecular Medicine Research Group, Robarts Research Institute, 1151 Richmond St, London, ON N6A 5B8, Canada"},{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine, University of Western Ontario, London, ON N6A 5B7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Seah","sequence":"additional","affiliation":[{"name":"J. Allyn Taylor Centre for Cell Biology, Molecular Medicine Research Group, Robarts Research Institute, 1151 Richmond St, London, ON N6A 5B8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn N.","family":"Whitehead","sequence":"additional","affiliation":[{"name":"Neuroscience Program, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5B7, Canada"},{"name":"Department of Anatomy and Cell Biology, Schulich School of Medicine, University of Western Ontario, London, ON N6A 5B7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0204-0255","authenticated-orcid":false,"given":"Stephen H.","family":"Pasternak","sequence":"additional","affiliation":[{"name":"Neuroscience Program, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5B7, Canada"},{"name":"J. Allyn Taylor Centre for Cell Biology, Molecular Medicine Research Group, Robarts Research Institute, 1151 Richmond St, London, ON N6A 5B8, Canada"},{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine, University of Western Ontario, London, ON N6A 5B7, Canada"},{"name":"Department of Clinical Neurological Sciences, Schulich School of Medicine, University of Western Ontario, London, ON N6A 5B7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Li, X., Feng, X., Sun, X., Hou, N., Han, F., and Liu, Y. (2022). Global, Regional, and National Burden of Alzheimer\u2019s Disease and Other Dementias, 1990\u20132019. Front. 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