Fig. 3

The role of SorLA in APP processing. A APP is directed from the trans-Golgi network (TGN) to the plasma membrane via the secretory pathway. APP molecules are either cleaved by α-secretase at the plasma membrane or recycled through endocytosis, and trafficked by early endosomes. There, APP is sequentially cleaved by β- and γ-secretases, thus generating Aβ monomers that are secreted to the extracellular space. B A model of SorLA involvement in the amyloid cascade. 1.-3. SorLA interacts with APP in TGN acting as a retention factor, which reduces α-secretase cleavage and secretion of sAPPα from the cell surface. 4.-7. In addition, SorLA forms a complex with APP that shuttles between the TGN and endosomes. The anterograde transport is dependent on SorLA’s interaction with AP-1 and GGA (4.), while the retrograde transport is determined by its binding to retromer or PACS1 (7.). SorLA’s interaction with retromer and SNX-27 in early endosomes additionally enables the sorting of APP along the recycling pathway to the plasma membrane (5.). This way, the sorting receptor is responsible for reducing the interaction between APP and β- and γ- secretases (5.). Importantly, binding of SorLA to BACE1 blocks the APP-BACE1 interaction, which reduces the production of secreted Aβ peptides (6.). Last but not least, SorLA also engages with Aβ peptides in endosomes and navigates them for the lysosomal degradation (8.)