Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production

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Tan, Jing Zhi A. | Fourriere, Lou | Wang, Jingqi | Perez, Franck | Boncompain, Gaëlle | Gleeson, Paul

Edité par CCSD ; American Society for Cell Biology -

International audience. 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 synthesised BACE1 and APP are transported along the secretory pathway, it is not known if 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. Using the RUSH system, we show that BACE1 is transported from the TGN 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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