Fig. 6.

Proposed role for sorLA in APP processing. Newly synthesized APP molecules traverse the Golgi (“1”) to the plasma membrane, where some are cleaved to sAPPα (“2”). Nonprocessed precursors endocytose from the cell surface into late endosomal compartments for processing into sAPPβ and Aβ (“3”). SorLA acts as a sorting receptor that traps APP in the Golgi (“1”), reducing the amount of precursors that reach the cell surface for processing. In addition, sorLA may also shuttle APP from early endosomes back to the Golgi, further reducing the extent of Aβ production in late endosomes (“4”). Consistent with this model, overexpression of sorLA in cultured cells further reduces transition of APP to the cell surface and suppresses processing into sAPPα and Aβ, whereas loss of sorLA expression in AD patients and in knockout mice results in accelerated trafficking of APP into processing pathways and in increased production of sAPPα and Aβ.