Figure 9

Model for the role of LRP10 in APP trafficking. LRP10 is transported from the Golgi to the plasma membrane in the secretory pathway independent of the DXXLL motifs. LRP10^wt is rapidly internalized from the cell surface into early endosomes where it is efficiently recycled back to the Golgi. LRP10 may also traffic directly from the TGN to the endosomes. LRP10^2DXXAA, which is unable to associate with GGAs and AP1/2, is slowly internalized from the plasma membrane and accumulates in the early endosomes, since it is incapable of recycling to the TGN. APP is constitutively transported to the plasma membrane and internalized in endosomes. Interaction of APP with LRP10^wt prolonged its presence in the TGN. LRP10 could trap APP in the TGN (1), reducing the amount of APP transported to the cell surface for non-amyloidogenic processing by α- and γ-secretases. In addition, LRP10 may shuttle APP from early endosome back to the TGN (2), reducing its amyloidogenic processing by β- and γ-secretases. LRP10^2DXXAA traps APP in endosomes (3), resulting in enhanced accessibility to amyloidogenic secretases and thus processing into Aβ.