p75 and TrkA receptor signaling independently regulate amyloid precursor protein mRNA expression, isoform composition, and protein secretion in PC12 cells.
The pheochromocytoma PC12 cell line was used as a model system to characterize the role of the p75 neurotrophin receptor (p75NTR) 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 outgrowth, APP mRNA expression, and APP secretion with maximal effects at concentrations known to saturate TrkA receptor binding. Displacement of NGF binding to p75NTR 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 p75NTR-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 outgrowth and APP secretion but not APP mRNA levels, which were decreased. These findings demonstrate that in PC12 cells expressing p75NTR and TrkA receptors, binding of NGF to the p75NTR is required to mediate NGF effects on cell morphology and APP metabolism. Furthermore, our data are consistent with NGF having specific effects on p75NTR not shared with other neurotrophins. Lastly, we have shown that specific activation of TrkA receptors--in contrast to p75NTR-associated signaling--stimulates neurite outgrowth and increases nonamyloidogenic secretory APP processing without increases in APP mRNA levels.
Department of Neurochemistry, Paul Flechsig Institute for Brain Research, Leipzig, Germany.
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Rossner
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Ueberham
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Schliebs
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JR
Perez-Polo
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Bigl
D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001798:Blood Proteins / Q000494:pharmacology; D015152:Blotting, Northern; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D018678:Cholinergic Agents / Q000494:pharmacology; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D000922:Immunotoxins / Q000494:pharmacology; D007536:Isomerism; D009699:N-Glycosyl Hydrolases; D009414:Nerve Growth Factors / Q000494:pharmacology; D016716:PC12 Cells; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000276:immunology / Q000378:metabolism* / Q000502:physiology*; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology
C085696:192 IgG-saporin; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; D000975:Antioxidants; D001798:Blood Proteins; D019208:Brain-Derived Neurotrophic Factor; D018678:Cholinergic Agents; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D000922:Immunotoxins; C064769:N-acetylsphingosine; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D054789:Ribosome Inactivating Proteins, Type 1; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D009699:N-Glycosyl Hydrolases; D000076985:Saporins; D013110:Sphingosine