APP regulates NGF receptor trafficking and NGF-mediated neuronal differentiation and survival.
β-Amyloid precursor protein (APP) is a key factor in Alzheimer's disease (AD) but its physiological function is largely undetermined. APP has been found to regulate retrograde transport of nerve growth factor (NGF), which plays a crucial role in mediating neuronal survival and differentiation. Herein, we reveal the mechanism underlying APP-mediated NGF trafficking, by demonstrating a direct interaction between APP and the two NGF receptors, TrkA and p75NTR. Downregulation of APP leads to reduced cell surface levels of TrkA/p75NTR and increased endocytosis of TrkA/p75NTR and NGF. In addition, APP-deficient cells manifest defects in neurite outgrowth and are more susceptible to Aβ-induced neuronal death at physiological levels of NGF. However, APP-deficient cells show better responses to NGF-stimulated differentiation and survival than control cells. This may be attributed to increased receptor endocytosis and enhanced activation of Akt and MAPK upon NGF stimulation in APP-deficient cells. Together, our results suggest that APP mediates endocytosis of NGF receptors through direct interaction, thereby regulating endocytosis of NGF and NGF-induced downstream signaling pathways for neuronal survival and differentiation.
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research and Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, China ; Neurodegenerative Disease Research Program, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
Yun-wu
YW
Zhang
Yaomin
Y
Chen
Yun
Y
Liu
Yingjun
Y
Zhao
Francesca-Fang
FF
Liao
Huaxi
H
Xu
D016564:Amyloid beta-Protein Precursor / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D047468:Immunoprecipitation; D051379:Mice; D020932:Nerve Growth Factor / Q000494:pharmacology*; D016716:PC12 Cells; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D016564:Amyloid beta-Protein Precursor; D020800:Receptor, Nerve Growth Factor; D020932:Nerve Growth Factor