The amyloid-beta precursor protein is phosphorylated via distinct pathways during differentiation, mitosis, stress, and degeneration.
Phosphorylation of amyloid-beta precursor protein (APP) at Thr(668) is a normal process linked to neurite extension and anterograde transport of vesicular cargo. By contrast, increased phosphorylation of APP is a pathological trait of Alzheimer's disease. APP is overexpressed in Down's syndrome, a condition that occasionally leads to increased APP phosphorylation, in cultured cells. Whether phosphorylation of APP in normal versus high APP conditions occurs by similar or distinct signaling pathways is not known. Here, we addressed this problem using brainstem-derived neurons (CAD cells). CAD cells that ectopically overexpress APP frequently show features of degenerating neurons. We found that, in degenerating cells, APP is hyperphosphorylated and colocalizes with early endosomes. By contrast, in normal CAD cells, phosphorylated APP (pAPP) is excluded from endosomes, and localizes to the Golgi apparatus and to transport vesicles within the neurites. Whereas the neuritic APP is phosphorylated by c-Jun NH(2)-terminal kinase through a pathway that is modulated by glycogen synthase kinase 3beta, the endosomal pAPP in degenerated CAD cells results from activation of cyclin-dependent kinase 5. Additional signaling pathways, leading to APP phosphorylation, become active during stress and mitosis. We conclude that distinct pathways of APP phosphorylation operate in proliferating, differentiating, stressed, and degenerating neurons.
Muresan
Zoia
Z
Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA. muresazo@umdnj.edu
Muresan
Virgil
V
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002451:Cell Compartmentation; D002454:Cell Differentiation; D002460:Cell Line; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors; D053938:DNA Fragmentation; D011992:Endosomes / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008938:Mitosis; D008954:Models, Biological; D009410:Nerve Degeneration / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport
D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C485750:MAPK8IP3 protein, human; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D051360:Cyclin-Dependent Kinase 5; D048031:JNK Mitogen-Activated Protein Kinases