Figure 2.

Retromer-mediated sorting in Alzheimer’s disease (AD). In microglia, retromer regulates the recycling pathway of phagocytic receptors to the cell surface for reuse, such as CD36 which can promote Aβ clearance. Retromer dysfunction decreases the recycle efficiency of phagocytic receptors, which leads to microglia abnormalities. BACE is response to cleave the amyloid precursor protein (APP) to Aβ (of varying lengths), and BACE is more activity in endosomes compartments because of low PH. In neuron, retromer retrievals its sorting receptor SorLA and SorLA from endosomes to TGN. (1) SorCS1 modulates retrograde TGN trafficking of APP from endosomal compartments resulting in increased APP localization to the TGN and decreased Aβ. (2) SorLA functions in slowing APP exit from the TGN into the secretory pathway whereby interacts with APP blocks the ability of APP to form homodimers, which are the preferred substrates of secretase. Secondly, SORL1 acts as a molecular link between APP and BACE and inhibits BACE interacts with APP in Golgi, which reduces cleavage of APP.