Processing of amyloid precursor protein (APP) by the β-secretase BACE1 is the initial step of the amyloidogenic pathway to generate amyloid-β (Aβ). Although newly synthesized BACE1 and APP are transported along the secretory pathway, it is not known whether BACE1 and APP share the same post-Golgi trafficking pathways or are partitioned into different transport routes. Here we demonstrate that BACE1 exits the Golgi in HeLa cells and primary neurons by a pathway distinct from the trafficking pathway for APP. By using the Retention Using Selective Hooks system, we show that BACE1 is transported from the trans-Golgi network to the plasma membrane in an AP-1- and Arf1/4-dependent manner. Subsequently, BACE1 is endocytosed to early and recycling endosomes. Perturbation of BACE1 post-Golgi trafficking results in an increase in BACE1 cleavage of APP and increased production of both Aβ40 and Aβ42. These findings reveal that Golgi exit of BACE1 and APP in primary neurons is tightly regulated, resulting in their segregation along different transport routes, which limits APP processing.
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- 30 January 2020 | International Journal of Molecular Sciences, Vol. 21, No. 3
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Downloads: 306Citations: 1History Submitted: 4 September 2019Revised: 1 November 2019Accepted: 15 November 2019
Information © 2020 Tan, Fourriere, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
Confocal microscopy was performed at the Biological Optical Microscopy Platform (BOMP) at the University of Melbourne. This work was supported by funding from the National Health and Medical Research Council of Australia (APP1163862). J.Z.A.T. and J.W. are supported by University of Melbourne International Postgraduate Awards. We gratefully acknowledge Fiona Houghton for reagents and expert technical advice, Wei Hong Toh and other members of the Gleeson laboratory for valuable discussions, Allison Van De Meene for maintenance of the spinning disk, and Ellie Cho for help with the quantitation.
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