Interleukin-1β enhances nucleotide-induced and α-secretase-dependent amyloid precursor protein processing in rat primary cortical neurons via up-regulation of the P2Y2receptor
| Autor: | Cheikh I. Seye, Gary A. Weisman, Qiongman Kong, Grace Y. Sun, Olga J. Baker, W. Gibson Wood, Troy S. Peterson, Jean M. Camden, Laurie Erb, Agnes Simonyi, Emily M. Stanley |
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| Rok vydání: | 2009 |
| Předmět: |
MAPK/ERK pathway
medicine.medical_specialty Interleukin-1beta Uridine Triphosphate Biology Transfection Biochemistry Article Rats Sprague-Dawley Receptors Purinergic P2Y2 Amyloid beta-Protein Precursor Cellular and Molecular Neuroscience chemistry.chemical_compound Internal medicine medicine Amyloid precursor protein Animals Humans Drug Interactions LY294002 RNA Messenger Enzyme Inhibitors Receptor Protein kinase C Cerebral Cortex Neurons Analysis of Variance Dose-Response Relationship Drug Nucleotides Receptors Purinergic P2 Kinase Embryo Mammalian Rats Up-Regulation Cell biology Endocrinology chemistry biology.protein Tetradecanoylphorbol Acetate Amyloid Precursor Protein Secretases Signal transduction Amyloid precursor protein secretase Signal Transduction |
| Zdroj: | Journal of Neurochemistry. 109:1300-1310 |
| ISSN: | 1471-4159 0022-3042 |
| Popis: | The heterologous expression and activation of the human P2Y(2) nucleotide receptor (P2Y(2)R) in human 1321N1 astrocytoma cells stimulates alpha-secretase-dependent cleavage of the amyloid precursor protein (APP), causing extracellular release of the non-amyloidogenic protein secreted amyloid precursor protein (sAPPalpha). To determine whether a similar response occurs in a neuronal cell, we analyzed whether P2Y(2)R-mediated production of sAPPalpha occurs in rat primary cortical neurons (rPCNs). In rPCNs, P2Y(2)R mRNA and receptor activity were virtually absent in quiescent cells, whereas overnight treatment with the pro-inflammatory cytokine interleukin-1beta (IL-1beta) up-regulated both P2Y(2)R mRNA expression and receptor activity by four-fold. The up-regulation of the P2Y(2)R was abrogated by pre-incubation with Bay 11-7085, an IkappaB-alpha phosphorylation inhibitor, which suggests that P2Y(2)R mRNA transcript levels are regulated through nuclear factor-kappa-B (NFkappaB) signaling. Furthermore, the P2Y(2)R agonist Uridine-5'-triphosphate (UTP) enhanced the release of sAPPalpha in rPCNs treated with IL-1beta or transfected with P2Y(2)R cDNA. UTP-induced release of sAPPalpha from rPCNs was completely inhibited by pre-treatment of the cells with the metalloproteinase inhibitor TACE inhibitor (TAPI-2) or the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, and was partially inhibited by the MAPK/extracellular signal-regulated kinase inhibitor U0126 and the protein kinase C inhibitor GF109203. These data suggest that P2Y(2)R-mediated release of sAPPalpha from cortical neurons is directly dependent on a disintegrin and metalloproteinase (ADAM) 10/17 and PI3K activity, whereas extracellular signal-regulated kinase 1/2 and PI3K activity may indirectly regulate APP processing. These results demonstrate that elevated levels of pro-inflammatory cytokines associated with neurodegenerative diseases, such as IL-1beta, can enhance non-amyloidogenic APP processing through up-regulation of the P2Y(2)R in neurons. |
| Databáze: | OpenAIRE |
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