p75 and TrkA receptor signaling independently regulate amyloid precursor protein mRNA expression, isoform composition, and protein secretion in PC12 cells

S. Roßner, U. Ueberham, R. Schliebs, J. R. Perez-Polo, V. Bigl

    Research output: Contribution to journalArticle

    44 Citations (Scopus)

    Abstract

    The pheochromocytoma PC12 cell line was used as a model system to characterize the role of the p75 neurotrophin receptor (p75(NTR)) and tyrosine kinase (Trk) A nerve growth factor (NGF) receptors on amyloid precursor protein (APP) expression and processing. NGF increased in a dose- dependent fashion neurite out-growth, APP mRNA expression, and APP secretion with maximal effects at concentrations known to saturate TrkA receptor binding. Displacement of NGF binding to p75(NTR) by addition of an excess of brain-derived neurotrophic factor abolished NGF's effects on neurite outgrowth and APP metabolism, whereas addition of brain-derived neurotrophic factor alone did not induce neurite outgrowth or affect APP mRNA or protein processing. However, treatment of PC12 cells with C2-ceramide, an analogue of ceramide, the endogenous product produced by the activity of p75(NTR)- activated sphingomyelinase, mimicked the effects of NGF on cell morphology and stimulation of both APP mRNA levels and APP secretion. Specific stimulation of TrkA receptors by receptor cross-linking, on the other hand, selectively stimulated neurite out-growth and APP secretion but not APP mRNA levels, which were decreased. These findings demonstrate that in PC12 cells expressing p75(NTR) and TrkA receptors, binding of NGF to the p75(NTR) is required to mediate NGF effects on cell morphology and APP metabolism. Furthermore, our data are consistent with NGF having specific effects on p75(NTR) not shared with other neurotrophins. Lastly, we have shown that specific activation of TrkA receptors - in contrast to p75(NTR)-associated signaling stimulates neurite outgrowth and increases nonamyloidogenic secretory APP processing without increases in APP mRNA levels.

    Original languageEnglish (US)
    Pages (from-to)757-766
    Number of pages10
    JournalJournal of Neurochemistry
    Volume71
    Issue number2
    StatePublished - Aug 1998

    Fingerprint

    trkA Receptor
    RNA Isoforms
    Amyloid beta-Protein Precursor
    PC12 Cells
    Protein Isoforms
    Nerve Growth Factor Receptor
    Nerve Growth Factor
    Messenger RNA
    Chemical analysis
    Proteins
    Brain-Derived Neurotrophic Factor
    Neurites
    Metabolism
    Processing
    Cells
    Nerve Growth Factor Receptors
    Sphingomyelin Phosphodiesterase
    Ceramides
    Nerve Growth Factors
    Growth

    Keywords

    • Amyloid precursor protein
    • Brain-derived neurotrophic factor
    • Ceramide
    • Nerve growth factor
    • p75(NTR)
    • TrkA

    ASJC Scopus subject areas

    • Biochemistry
    • Cellular and Molecular Neuroscience

    Cite this

    p75 and TrkA receptor signaling independently regulate amyloid precursor protein mRNA expression, isoform composition, and protein secretion in PC12 cells. / Roßner, S.; Ueberham, U.; Schliebs, R.; Perez-Polo, J. R.; Bigl, V.

    In: Journal of Neurochemistry, Vol. 71, No. 2, 08.1998, p. 757-766.

    Research output: Contribution to journalArticle

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    abstract = "The pheochromocytoma PC12 cell line was used as a model system to characterize the role of the p75 neurotrophin receptor (p75(NTR)) and tyrosine kinase (Trk) A nerve growth factor (NGF) receptors on amyloid precursor protein (APP) expression and processing. NGF increased in a dose- dependent fashion neurite out-growth, APP mRNA expression, and APP secretion with maximal effects at concentrations known to saturate TrkA receptor binding. Displacement of NGF binding to p75(NTR) by addition of an excess of brain-derived neurotrophic factor abolished NGF's effects on neurite outgrowth and APP metabolism, whereas addition of brain-derived neurotrophic factor alone did not induce neurite outgrowth or affect APP mRNA or protein processing. However, treatment of PC12 cells with C2-ceramide, an analogue of ceramide, the endogenous product produced by the activity of p75(NTR)- activated sphingomyelinase, mimicked the effects of NGF on cell morphology and stimulation of both APP mRNA levels and APP secretion. Specific stimulation of TrkA receptors by receptor cross-linking, on the other hand, selectively stimulated neurite out-growth and APP secretion but not APP mRNA levels, which were decreased. These findings demonstrate that in PC12 cells expressing p75(NTR) and TrkA receptors, binding of NGF to the p75(NTR) is required to mediate NGF effects on cell morphology and APP metabolism. Furthermore, our data are consistent with NGF having specific effects on p75(NTR) not shared with other neurotrophins. Lastly, we have shown that specific activation of TrkA receptors - in contrast to p75(NTR)-associated signaling stimulates neurite outgrowth and increases nonamyloidogenic secretory APP processing without increases in APP mRNA levels.",
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