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  • Title: Ligand-dependent activation of the chimeric tumor necrosis factor receptor-amyloid precursor protein (APP) reveals increased APP processing and suppressed neuronal differentiation.
    Author: Sim PL, Heese K.
    Journal: Neurosignals; 2010; 18(1):9-23. PubMed ID: 19786811.
    Abstract:
    The β-amyloid precursor protein (APP) is a type I transmembrane protein whose functions and metabolic processing have been implicated in the pathogenesis of Alzheimer's disease (AD). APP's physical resemblance as a glycosylated receptor and the presence of several conserved motifs which are characteristics of a membrane-associated receptor has prompted interest to study and understand the role of downstream signaling events mediated by the activation of APP during both physiological and pathological conditions. Efforts to elucidate the mechanisms of APP signaling have not been conclusive. In order to further characterize the intracellular signaling activities of APP, we have constructed a chimeric APP receptor which is made up of the extracellular domain of human tumor necrosis factor receptor superfamily, member 1B (TNFRSF1B), the membrane-spanning segment of human APP(770) isoform's β-cleaved carboxyl-terminal fragment (C99), and the green fluorescent protein (GFP) tagged to the carboxyl-terminus of C99. The mammalian rat pheochromocytoma (PC12) cell line is used as the cellular model for transfection of this TNFRSF1B-APP-GFP (TAF) fusion receptor. Ligand-specific stimulation of this TAF receptor using human recombinant TNF reveals the induction of cytoplasmic TAF phosphorylation on Thr743 (numbering for APP(770) isoform) and an elevated release of APP intracellular domains (AICDs). Time-lapse microscopy shows the trafficking of GFP-tagged AICDs into the nucleus upon TAF receptor activation. The increased presence of AICDs is believed to suppress neuronal differentiation of PC12 cells in response to nerve growth factor treatment, by negatively regulating the levels of p53, cyclin D1 and phosphorylation of the signal transducer and activator of transcription STAT3.
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