Adaptor complex AP2/PICALM, through interaction with LC3, targets Alzheimer's APP-CTF for terminal degradation via autophagy.
The hallmarks of Alzheimer's disease (AD) are the aggregates of amyloid-β (Aβ) peptides and tau protein. Autophagy is a major cellular pathway leading to the removal of aggregated proteins. We have reported recently that autophagy was responsible for amyloid precursor protein cleaved C-terminal fragment (APP-CTF) degradation and amyloid β clearance in an Atg5-dependent manner. Here we aimed to elucidate the molecular mechanism by which autophagy mediates the degradation of APP-CTF and the clearance of amyloid β. Through affinity purification followed by mass spectrum analysis, we identified adaptor protein (AP) 2 together with phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) as binding proteins of microtubule-associated protein 1 light chain 3 (LC3). Further analysis showed that AP2 regulated the cellular levels of APP-CTF. Knockdown of AP2 reduced autophagy-mediated APP-CTF degradation. Immunoprecipitation and live imaging analysis demonstrated that AP2 and PICALM cross-link LC3 with APP-CTF. These data suggest that the AP-2/PICALM complex functions as an autophagic cargo receptor for the recognition and shipment of APP-CTF from the endocytic pathway to the LC3-marked autophagic degradation pathway. This molecular mechanism linking AP2/PICALM and AD is consistent with genetic evidence indicating a role for PICALM as a risk factor for AD.
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
Yuan
Y
Tian
Jerry C
JC
Chang
Emily Y
EY
Fan
Marc
M
Flajolet
Paul
P
Greengard
D033962:Adaptor Protein Complex 2 / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D006367:HeLa Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D034041:Monomeric Clathrin Assembly Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D012307:Risk Factors
C545487:APP protein, human; C502778:ATG5 protein, human; D033962:Adaptor Protein Complex 2; D016564:Amyloid beta-Protein Precursor; D000071187:Autophagy-Related Protein 5; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human
aggregate removal; endocytosis; trafficking