Qiongman Kong and Troy S. Peterson contributed equally to this work.
Interleukin-1β enhances nucleotide-induced and α-secretase-dependent amyloid precursor protein processing in rat primary cortical neurons via up-regulation of the P2Y2 receptor
Article first published online: 20 MAR 2009
© 2009 The Authors. Journal Compilation © 2009 International Society for Neurochemistry
Journal of Neurochemistry
Volume 109, Issue 5, pages 1300–1310, June 2009
How to Cite
Kong, Q., Peterson, T. S., Baker, O., Stanley, E., Camden, J., Seye, C. I., Erb, L., Simonyi, A., Wood, W. G., Sun, G. Y. and Weisman, G. A. (2009), Interleukin-1β enhances nucleotide-induced and α-secretase-dependent amyloid precursor protein processing in rat primary cortical neurons via up-regulation of the P2Y2 receptor. Journal of Neurochemistry, 109: 1300–1310. doi: 10.1111/j.1471-4159.2009.06048.x
- Issue published online: 12 MAY 2009
- Article first published online: 20 MAR 2009
- Received November 21, 2008; revised manuscript received March 4, 2009; accepted March 13, 2009.
- Alzheimer's disease;
- amyloid precursor protein;
- primary neuron
The heterologous expression and activation of the human P2Y2 nucleotide receptor (P2Y2R) in human 1321N1 astrocytoma cells stimulates α-secretase-dependent cleavage of the amyloid precursor protein (APP), causing extracellular release of the non-amyloidogenic protein secreted amyloid precursor protein (sAPPα). To determine whether a similar response occurs in a neuronal cell, we analyzed whether P2Y2R-mediated production of sAPPα occurs in rat primary cortical neurons (rPCNs). In rPCNs, P2Y2R mRNA and receptor activity were virtually absent in quiescent cells, whereas overnight treatment with the pro-inflammatory cytokine interleukin-1β (IL-1β) up-regulated both P2Y2R mRNA expression and receptor activity by four-fold. The up-regulation of the P2Y2R was abrogated by pre-incubation with Bay 11-7085, an IκB-α phosphorylation inhibitor, which suggests that P2Y2R mRNA transcript levels are regulated through nuclear factor-κ-B (NFκB) signaling. Furthermore, the P2Y2R agonist Uridine-5′-triphosphate (UTP) enhanced the release of sAPPα in rPCNs treated with IL-1β or transfected with P2Y2R cDNA. UTP-induced release of sAPPα 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 P2Y2R-mediated release of sAPPα 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-1β, can enhance non-amyloidogenic APP processing through up-regulation of the P2Y2R in neurons.