[HTML][HTML] APP regulates NGF receptor trafficking and NGF-mediated neuronal differentiation and survival

Y Zhang, Y Chen, Y Liu, Y Zhao, FF Liao, H Xu - PloS one, 2013 - journals.plos.org
Y Zhang, Y Chen, Y Liu, Y Zhao, FF Liao, H Xu
PloS one, 2013journals.plos.org
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 …
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.
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