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Kong, Q, Peterson, TS, Baker, O, Stanley, E, Camden, J, Seye, CI, Erb, L, Simonyi, A, Wood, WG, Sun, GY and Weisman, GA (2009) Interleukin-1beta enhances nucleotide-induced and alpha-secretase-dependent amyloid precursor protein processing in rat primary cortical neurons via up-regulation of the P2Y(2) receptor. J. Neurochem. 109:1300-10

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.

PubMed PMC2710802 Online version:10.1111/j.1471-4159.2009.06048.x

Amyloid Precursor Protein Secretases/metabolism; Amyloid beta-Protein Precursor/metabolism; Analysis of Variance; Animals; Cerebral Cortex/cytology; Dose-Response Relationship, Drug; Drug Interactions; Embryo, Mammalian; Enzyme Inhibitors/pharmacology; Humans; Interleukin-1beta/pharmacology; Neurons/drug effects; Neurons/metabolism; Nucleotides/pharmacology; RNA, Messenger/metabolism; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2/genetics; Receptors, Purinergic P2/metabolism; Receptors, Purinergic P2Y2; Signal Transduction/drug effects; Tetradecanoylphorbol Acetate/analogs & derivatives; Tetradecanoylphorbol Acetate/pharmacology; Transfection/methods; Up-Regulation/drug effects; Uridine Triphosphate/pharmacology