{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:19:26Z","timestamp":1785406766924,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,17]]},"group-title":"Neuroscience","reference-count":87,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01DK117308"],"award-info":[{"award-number":["R01DK117308"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U54MD007601-38S1"],"award-info":[{"award-number":["U54MD007601-38S1"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P20GM103457"],"award-info":[{"award-number":["P20GM103457"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30CA071789"],"award-info":[{"award-number":["P30CA071789"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R24GM137786"],"award-info":[{"award-number":["R24GM137786"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Hawaii Community Foundation","award":["19ADVC-95450"],"award-info":[{"award-number":["19ADVC-95450"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,17]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>Intracellular trafficking of amyloid precursor protein (APP) critically influences amyloidogenic processing, yet the mechanisms regulating this pathway remain incompletely defined. The exocyst is a highly conserved, insulin-responsive, eight-protein Rab effector complex that directs intracellular transport vesicle targeting and docking. We identified APP in a proteomics screen of neuronal cell surface proteins altered after chemical inhibition of exocyst activity. In SH-SY5Y cells expressing a mutant APP that enhances amyloidogenic processing, RNAi-mediated silencing of exocyst subunits significantly decreased sAPP and A\u03b2 secretion, leading to significant intracellular APP accumulation. We found high-resolution co-localization of APP with exocyst subunits in soma and neurites of differentiated human SH-SY5Y neurons and mouse primary hippocampal neurons, and live-cell TIRF microscopy identified highly coordinated movement between fluorescently-tagged exocyst and APP proteins. These interactions were confirmed in these cells and in mouse brain histological sections by proximity ligation assays (PLAs) demonstrating close (&lt;40nm) APP-EXOC5 association. To examine if exocyst activity in neurons is regulated by insulin, as it is in adipocytes and muscle, we generated a SH-SY5Y cell line with pHluorin-tagged GLUT4. Inhibition of the exocyst prevented exocytosis of GLUT4 to the plasma membrane in response to insulin. Additionally, using PLAs in mouse primary hippocampal neurons and SH-SY5Y neurons, we found that GLUT4-EXOC5 associations were increased by insulin signaling, but APP-EXOC5 associations were markedly reduced, indicating insulin-dependent retargeting of the exocyst complex away from APP+ vesicles towards GLUT+ vesicles. All together, these data identify the exocyst as a novel insulin-regulated mediator of neuronal APP trafficking and A\u03b2 secretion.<\/jats:p>\n                <jats:sec>\n                  <jats:title>In Brief<\/jats:title>\n                  <jats:p>We show that the insulin-responsive exocyst regulates amyloidogenic processing of APP in neurons and that insulin signaling shifts the exocyst away from APP trafficking to promote the translocation of GLUT4-containing vesicles to the plasma membrane of neurons.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.14.717551","type":"posted-content","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T19:00:16Z","timestamp":1776452416000},"source":"Crossref","is-referenced-by-count":0,"title":["The exocyst is an insulin-sensitive regulator of amyloid precursor protein trafficking and amyloid-beta generation in neurons"],"prefix":"10.64898","author":[{"given":"Chantell","family":"Balaan","sequence":"first","affiliation":[{"name":"Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawai\u02bbi at M\u0101noa, Honolulu, HI 96813"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geetika Y.","family":"Patwardhan","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawai\u02bbi at M\u0101noa, Honolulu, HI 96813"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel K.","family":"Sachs","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawai\u02bbi at M\u0101noa, Honolulu, HI 96813"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Kumasaka","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawai\u02bbi at M\u0101noa, Honolulu, HI 96813"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swasthita","family":"Sadagopan","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawai\u02bbi at M\u0101noa, Honolulu, HI 96813"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shion","family":"Aou","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawai\u02bbi at M\u0101noa, Honolulu, HI 96813"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda J.","family":"Lee","sequence":"additional","affiliation":[{"name":"Math and Sciences Department, Kapiolani Community College, Honolulu, Hawaii 96816, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke T.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawai\u02bbi at M\u0101noa, Honolulu, HI 96813"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian E.","family":"Hew","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology, John A. 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