Amyloid precursor protein traffics from the Golgi directly to early endosomes in an Arl5b‐ and AP4‐dependent pathway. (30th January 2017)

• Record Type: Journal Article
• Authors: Toh, Wei Hong; Tan, Jing Zhi A.; Zulkefli, Khalisah L.; Houghton, Fiona J.; Gleeson, Paul A.
• Is Part Of: Traffic. Volume 18:Number 3(2017)
• Page Start: 159
• Page End: 175
• Publication Date: 2017-01-30
• Subjects: amyloid‐β peptide -- amyloid precursor protein -- anterograde transport -- AP4 -- Arl5b -- early endosomes -- trans‐Golgi network; Biological transport -- Periodicals; 571.6
• DOI: 10.1111/tra.12465
• Languages: English
• ISSNs: 1398-9219

Abstract

Abstract : The intracellular trafficking and proteolytic processing of the membrane‐bound amyloid precursor protein (APP) are coordinated events leading to the generation of pathogenic amyloid‐beta (Aβ) peptides. The membrane transport of newly synthesized APP from the Golgi to the endolysosomal system is not well defined, yet it is likely to be critical for regulating its processing by β‐secretase (BACE1) and γ‐secretase. Here, we show that the majority of newly synthesized APP is transported from the trans ‐Golgi network (TGN) directly to early endosomes and then subsequently to the late endosomes/lysosomes with very little transported to the cell surface. We show that Arl5b, a small G protein localized to the TGN, and AP4 are essential for the post‐Golgi transport of APP to early endosomes. Arl5b is physically associated with AP4 and is required for the recruitment of AP4, but not AP1, to the TGN. Depletion of either Arl5b or AP4 results in the accumulation of APP, but not BACE1, in the Golgi, and an increase in APP processing and Aβ secretion. These findings demonstrate that APP is diverted from BACE1 at the TGN for direct transport to early endosomes and that the TGN represents a site for APP processing with the subsequent secretion of Aβ. Abstract : The membrane trafficking of newly synthesized amyloid precursor protein (APP) from the Golgi to the endolysosomal system is not well defined, yet it is critical for understanding the processing of APP. We demonstrate that the small G protein Arl5b recruits the adaptor complex AP4 to the trans ‐Golgi network (TGN) that regulates APP transport from the TGN directly to early endosomes. Our findings also show that the post‐Golgi trafficking of newly synthesized APP is relevant for the regulation of amyloid β production.