The exocyst is an insulin-sensitive regulator of amyloid precursor protein trafficking and amyloid-beta generation in neurons

Balaan, C.; Patwardhan, G. Y.; Sachs, R. K.; Kumasaka, H.; Sadagopan, S.; Aou, S.; Lee, A. J.; Nelson, L. T.; Hew, B. E.; Owens, J. B.; Polgar, N.; Ortega, M. A.; Nichols, R. A.; Fogelgren, B.

doi:10.64898/2026.04.14.717551

bioRxiv · 10.64898/2026.04.14.717551

The exocyst is an insulin-sensitive regulator of amyloid precursor protein trafficking and amyloid-beta generation in neurons

Balaan, C.·Patwardhan, G. Y.·Sachs, R. K.·Kumasaka, H.·Sadagopan, S.·Aou, S.·Lee, A. J.·Nelson, L. T.·Hew, B. E.·Owens, J. B.·Polgar, N.·Ortega, M. A.·Nichols, R. A.·Fogelgren, B.

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Abstract

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{beta} 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 (<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{beta} secretion. In BriefWe 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.

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Balaan, C., Patwardhan, G. Y., Sachs, R. K., Kumasaka, H., Sadagopan, S., Aou, S., Lee, A. J., Nelson, L. T., Hew, B. E., Owens, J. B., Polgar, N., Ortega, M. A., Nichols, R. A., Fogelgren, B.. 2026-04-17. The exocyst is an insulin-sensitive regulator of amyloid precursor protein trafficking and amyloid-beta generation in neurons. https://doi.org/10.64898/2026.04.14.717551

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