APP is phosphorylated by TrkA and regulates NGF/TrkA signaling

Institute of Cellular Biology and Neurobiology, National Council of Research of Rome, 00143 Rome, Italy.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/2011; 31(33):11756-61. DOI: 10.1523/JNEUROSCI.1960-11.2011
Source: PubMed

ABSTRACT The pathogenic model of Alzheimer's disease (AD) posits that aggregates of amyloid β, a product of amyloid precursor protein (APP) processing, cause dementia. However, alterations of normal APP functions could contribute to AD pathogenesis, and it is therefore important to understand the role of APP. APP is a member of a gene family that shows functional redundancy as documented by the evidence that single knock-out mice are viable, whereas mice with combined deletions of APP family genes die shortly after birth. A residue in the APP intracellular region, Y(682), is indispensable for these essential functions of APP. It is therefore important to identify pathways that regulate phosphorylation of Y(682) as well as the role of Y(682) in vivo. TrkA is associated with both phosphorylation of APP-Y(682) and alteration of APP processing, suggesting that tyrosine phosphorylation of APP links APP processing and neurotrophic signaling to intracellular pathways associated with cellular differentiation and survival. Here we have tested whether the NGF/TrkA signaling pathway is a physiological regulator of APP phosphorylation. We find that NGF induces tyrosine phosphorylation of APP, and that APP interacts with TrkA and this interaction requires Y(682). Unpredictably, we also uncover that APP, and specifically Y(682), regulates activation of the NGF/TrkA signaling pathway in vivo, the subcellular distribution of TrkA and the sensitivity of neurons to the trophic action of NGF. This evidence suggests that these two membrane protein's functions are strictly interconnected and that the NGF/TrkA signaling pathway is involved in AD pathogenesis and can be used as a therapeutic target.

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Available from: Carmela Matrone, Sep 29, 2015
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    • "APP is involved in synapse formation, dendritic spine formation, synaptic transmission, neurites outgrowth, learning and memory, motility and development [13]. Though all APP metabolites have biological functions [14]–[20], phenomenological observations underline the key physiological and pathological role of the APP intracellular domain [21]–[26]. Mutation of single APP intracellular residues can have dramatically opposite effects. For example, mice carrying the Y682G (using the APP-695 isoform numbering) mutation in the intracellular domain, present functional deficits similar to that of APP KO mice, including cognitive and neuromuscular junctions deficits [23], [25]. "
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    ABSTRACT: Amyloid Precursor Protein (APP) is a type I membrane protein that undergoes extensive processing by secretases, including BACE1. Although mutations in APP and genes that regulate processing of APP, such as PSENs and BRI2/ITM2B, cause dementias, the normal function of APP in synaptic transmission, synaptic plasticity and memory formation is poorly understood. To grasp the biochemical mechanisms underlying the function of APP in the central nervous system, it is important to first define the sub-cellular localization of APP in synapses and the synaptic interactome of APP. Using biochemical and electron microscopy approaches, we have found that APP is localized in pre-synaptic vesicles, where it is processed by Bace1. By means of a proteomic approach, we have characterized the synaptic interactome of the APP intracellular domain. We focused on this region of APP because in vivo data underline the central funtional and pathological role of the intracellular domain of APP. Consistent with the expression of APP in pre-synaptic vesicles, the synaptic APP intracellular domain interactome is predominantly constituted by pre-synaptic, rather than post-synaptic, proteins. This pre-synaptic interactome of the APP intracellular domain includes proteins expressed on pre-synaptic vesicles such as the vesicular SNARE Vamp2/Vamp1 and the Ca2+ sensors Synaptotagmin-1/Synaptotagmin-2, and non-vesicular pre-synaptic proteins that regulate exocytosis, endocytosis and recycling of pre-synaptic vesicles, such as target-membrane-SNAREs (Syntaxin-1b, Syntaxin-1a, Snap25 and Snap47), Munc-18, Nsf, α/β/γ-Snaps and complexin. These data are consistent with a functional role for APP, via its carboxyl-terminal domain, in exocytosis, endocytosis and/or recycling of pre-synaptic vesicles.
    PLoS ONE 09/2014; 9(9):e108576. DOI:10.1371/journal.pone.0108576 · 3.23 Impact Factor
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    • "Therefore, The activation and phosphorylation of CREB was associated with APP processing and Aβ desposits, which had the same tendency with our results that phosphorylation of CREB was related with the decreased levels of APP and Aβ (shown in Figs. 5 and 6). Moreover, Matrone et al. [49] found that NGF induced phosphorylation of APP by TrkA and regulated NGF/TrkA signaling, and consequentially affected the differentiation and survival of neurons. Therefore, NGF had close relationship with APP and Aβ deposits. "
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    ABSTRACT: Alzheimer's disease (AD) is pathologically characterized by deposition of β-amyloid (Aβ) peptides, which closely correlates with the balance of nerve growth factor (NGF)-related TrkA/p75(NTR) signaling. (-)-Epigallocatechin-3-gallate (EGCG) is used for prevention and treatment of many neurodegenerative diseases, including AD. However, whether the neuroprotective effects of EGCG treatment were via modulating the balance of TrkA/p75(NTR) signaling was still unknown. In this study, we found that EGCG treatment (2 mg · kg (-1) · day (-1)) dramatically ameliorated the cognitive impairments, reduced the overexpressions of Aβ(1-40) and amyloid precursor protein (APP), and inhibited the neuronal apoptosis in the APP/PS1 mice. Interestingly, the EGCG treatment enhanced the relative expression level of NGF by increasing the NGF/proNGF ratio in the APP/PS1 mice. Moreover, after EGCG treatment, TrkA signaling was activated by increasing the phosphorylation of TrkA following the increased phosphorylation of c-Raf, ERK1/2, and cAMP response element-binding protein (CREB), simultaneously the p75(NTR) signaling was significantly inhibited by decreasing the p75(ICD) expression, JNK2 phosphorylation, and cleaved-caspase 3 expression, so that the Aβ deposits and neuronal apoptosis in the hippocampus were inhibited.
    Molecular Neurobiology 12/2013; 49(3). DOI:10.1007/s12035-013-8608-2 · 5.14 Impact Factor
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    • "For example, our present study, as well as others' has shown that APP can interact with both TrkA and p75NTR [25], [26]. One study suggested that the interaction between APP and TrkA requires the tyrosine residue at APP position 682 (Y682, numbering based on APP695 isoform) [26]. APP-Y682 has been shown to be important for the function and processing of APP [35]. "
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    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.
    PLoS ONE 11/2013; 8(11):e80571. DOI:10.1371/journal.pone.0080571 · 3.23 Impact Factor
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