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. 2017 Mar 1;10:54. doi: 10.3389/fnmol.2017.00054

Figure 2.

Figure 2

Lipoprotein receptors modulate amyloid precursor protein (APP) trafficking and processing in neurons. Neurons are the major source of Aβ (depicted as green droplets) in the brain. APP (green), all core LDL receptor family members as well as the more distant member SorLA contains at least one NPxY-motif, which acts as a docking site for PTB-domains of intracellular adaptor/scaffold proteins. Both Fe65 and Dab1 bind APP, as well as a number of LDL receptor family members (red and orange), via their PTB-domains. The simultaneous binding of these intracellular adaptor/scaffolding proteins to the NPxY motifs of APP and LDL receptors coordinate their intracellular trafficking, thus regulating APP localization and processing. The adapter/scaffold proteins control the speed of endocytosis of the receptors in that Fe65 and Dab1 binding to APP masks the endocytosis signal of APP, resulting in the surface retention of APP. This increases the exposure of APP to α-secretase (α), which cleaves APP inside the Aβ region (dark green) to release a soluble APPα (sAPPα) fragment and ultimately preventing the production of Aβ. Importantly, Lrp1 and Lrp1b (both orange in the diagram) have drastically different rates of endocytosis, with the internalization rate of Lrp1 exceeding that of Lrp1b by many-fold. Both bind Fe65, connecting them in a complex APP, and have opposite effects on APP processing. The fast endocytosis rate of Lrp1 increases the exposure of APP to the endosomal β- (BACE1, β) and γ-secretase (γ), producing Aβ (green tears) and soluble APPβ (sAPPβ) fragment. Another intraendosomal sorting receptor of the LDL receptor family, SorLA, can bind and reroute receptors from the endosome back to the trans-Golgi network (TGN), where it is either sequestered, sorted back to the cell surface, or sent to the lysosome for degradation. Apoer2, which also recycles slowly, binds Fe65 via its NPxY-motif, promoting APP surface stability and decrease amyloidogenic processing. Additionally, simultaneous binding of the secreted, extracellular ligand, F-spondin, to the ECDs of APP and Apoer2 also promotes APP stability at the surface.