The convergence of endosomal and autophagosomal pathways

Abstract

We have reported previously that autophagy is responsible for amyloidprecursor potein-C-terminal fragment (APP-CTF) degradation and thereforeAβ clearance. To elucidate the underlying mechanism, using LC3 affinitypurification and mass spectrometry analysis, immunoprecipitation(IP), as well as live imaging analysis, we identified and demonstratedthat the adaptor-related protein complex 2 (AP2) and PICALM (phosphatidylinositolbinding clathrin assembly protein) are in a complex with LC3 andAPP-CTF. Taken together, this new set of data suggests that the AP2-PICALMcomplex functions as an autophagic cargo receptor for the recognitionand shipment of APP-CTF from the endocytic pathway to the LC3-dependentautophagic degradation pathway. Interestingly this AP2-LC3 connectionseems to be involved in chemically-induced APP-CTF clearance as weobserved using the small compound SMER28. The effect observed followingSMER28 was significantly reduced after silencing AP2. While morework is required to elucidate the detailed molecular mechanisms involved,our actual data suggest that there is some level of specificity inthe steps mentioned above.