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. that Aβ can be generated in the endosomal system, 3 considered to arise from the internalization of APP from the PM, and there is general consensus that under normal conditions the early endosome is a major site of APP processing by BACE1. [4][5][6][7] Although less well characterized there are also several reports which have indicated that Aβ can be generated in the secretory pathway, [8][9][10] in particular the trans-Golgi network (TGN). 11-13APP is synthesized in the endoplasmic reticulum (ER) and then transported to the Golgi where it is glycosylated and the mature glycoprotein then exits the Golgi at the TGN.

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