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APP regulates NGF receptor trafficking and NGF-mediated neuronal differentiation and survival.

Zhang YW, Chen Y, Liu Y, Zhao Y, Liao FF, Xu H - PLoS ONE (2013)

Bottom Line: APP has been found to regulate retrograde transport of nerve growth factor (NGF), which plays a crucial role in mediating neuronal survival and differentiation.Downregulation of APP leads to reduced cell surface levels of TrkA/p75NTR and increased endocytosis of TrkA/p75NTR and NGF.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT
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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Related in: MedlinePlus

APP deficiency enhances activation of Akt and MAPK upon NGF treatment.PC12 cells stably expressing APP shRNA and control cells expressing scrambled control (SC) shRNA were treated with 100 ng/mL NGF for the indicated time periods. Equal protein amounts of cell lysates were subjected to Western blotting to measure phosphorylation (p)/activation of Akt and MAPK. Protein levels were quantified by densitometry and normalized to those of controls for comparison (set as one arbitrary unit). Error bars indicate SEM, n = 3.
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pone-0080571-g004: APP deficiency enhances activation of Akt and MAPK upon NGF treatment.PC12 cells stably expressing APP shRNA and control cells expressing scrambled control (SC) shRNA were treated with 100 ng/mL NGF for the indicated time periods. Equal protein amounts of cell lysates were subjected to Western blotting to measure phosphorylation (p)/activation of Akt and MAPK. Protein levels were quantified by densitometry and normalized to those of controls for comparison (set as one arbitrary unit). Error bars indicate SEM, n = 3.

Mentions: Neuronal survival and differentiation are regulated by the NGF-activated downstream signaling pathways PI3k/Akt and MAPK, respectively [19], [20], [21]. Herein, we found that when cells were treated with NGF, phosphorylation of both Akt and MAPK for their activation was dramatically elevated (Figure 4): in control cells, NGF treatments for 1, 3 and 5 d promoted Akt phosphorylation for 1.7, 1.6 and 1.4 folds, respectively, and promoted MAPK phosphorylation for 3.8, 2.5 and 2.4 folds, respectively; while in APP downregulated cells, NGF treatments for 1, 3 and 5 d promoted Akt phosphorylation for 2.8, 2.9 and 2.4 folds, respectively, and promoted MAPK phosphorylation for 8.7, 6.6 and 4.6 folds, respectively. However, when we compared the change of Akt and MAPK phosphorylation in control and in APP downregulated cells, we noticed that the increased levels of both Akt and MAPK phosphorylation were much higher in APP downregulated cells than in control cells (Figure 4), which is consistent with the more significant survival and differentiation responses to NGF in these cells.


APP regulates NGF receptor trafficking and NGF-mediated neuronal differentiation and survival.

Zhang YW, Chen Y, Liu Y, Zhao Y, Liao FF, Xu H - PLoS ONE (2013)

APP deficiency enhances activation of Akt and MAPK upon NGF treatment.PC12 cells stably expressing APP shRNA and control cells expressing scrambled control (SC) shRNA were treated with 100 ng/mL NGF for the indicated time periods. Equal protein amounts of cell lysates were subjected to Western blotting to measure phosphorylation (p)/activation of Akt and MAPK. Protein levels were quantified by densitometry and normalized to those of controls for comparison (set as one arbitrary unit). Error bars indicate SEM, n = 3.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3815101&req=5

pone-0080571-g004: APP deficiency enhances activation of Akt and MAPK upon NGF treatment.PC12 cells stably expressing APP shRNA and control cells expressing scrambled control (SC) shRNA were treated with 100 ng/mL NGF for the indicated time periods. Equal protein amounts of cell lysates were subjected to Western blotting to measure phosphorylation (p)/activation of Akt and MAPK. Protein levels were quantified by densitometry and normalized to those of controls for comparison (set as one arbitrary unit). Error bars indicate SEM, n = 3.
Mentions: Neuronal survival and differentiation are regulated by the NGF-activated downstream signaling pathways PI3k/Akt and MAPK, respectively [19], [20], [21]. Herein, we found that when cells were treated with NGF, phosphorylation of both Akt and MAPK for their activation was dramatically elevated (Figure 4): in control cells, NGF treatments for 1, 3 and 5 d promoted Akt phosphorylation for 1.7, 1.6 and 1.4 folds, respectively, and promoted MAPK phosphorylation for 3.8, 2.5 and 2.4 folds, respectively; while in APP downregulated cells, NGF treatments for 1, 3 and 5 d promoted Akt phosphorylation for 2.8, 2.9 and 2.4 folds, respectively, and promoted MAPK phosphorylation for 8.7, 6.6 and 4.6 folds, respectively. However, when we compared the change of Akt and MAPK phosphorylation in control and in APP downregulated cells, we noticed that the increased levels of both Akt and MAPK phosphorylation were much higher in APP downregulated cells than in control cells (Figure 4), which is consistent with the more significant survival and differentiation responses to NGF in these cells.

Bottom Line: APP has been found to regulate retrograde transport of nerve growth factor (NGF), which plays a crucial role in mediating neuronal survival and differentiation.Downregulation of APP leads to reduced cell surface levels of TrkA/p75NTR and increased endocytosis of TrkA/p75NTR and NGF.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus