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

Qiongman Kong, Troy S. Peterson, Olga Baker, Emily Stanley, Jean Camden, Cheikh Seye, Laurie Erb, Agnes Simonyi, W. Gibson Wood, Grace Y. Sun, Gary A. Weisman

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

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 P2Y 2R was abrogated by pre-incubation with Bay 11-7085, an IκB-α phosphorylation inhibitor, which suggests that P2Y 2R 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.

Original languageEnglish (US)
Pages (from-to)1300-1310
Number of pages11
JournalJournal of Neurochemistry
Volume109
Issue number5
DOIs
StatePublished - Jun 2009
Externally publishedYes

Fingerprint

Purinergic P2Y2 Receptors
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor
Interleukin-1
Neurons
Rats
Up-Regulation
Nucleotides
Phosphatidylinositol 3-Kinase
Processing
Uridine Triphosphate
Uridine
Metalloproteases
Messenger RNA
Neurodegenerative diseases
Cytokines
Disintegrins
Phosphorylation
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Mitogen-Activated Protein Kinase 3

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • P2Y
  • Primary neuron

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

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. / Kong, Qiongman; Peterson, Troy S.; Baker, Olga; Stanley, Emily; Camden, Jean; Seye, Cheikh; Erb, Laurie; Simonyi, Agnes; Wood, W. Gibson; Sun, Grace Y.; Weisman, Gary A.

In: Journal of Neurochemistry, Vol. 109, No. 5, 06.2009, p. 1300-1310.

Research output: Contribution to journalArticle

Kong, Qiongman ; Peterson, Troy S. ; Baker, Olga ; Stanley, Emily ; Camden, Jean ; Seye, Cheikh ; Erb, Laurie ; Simonyi, Agnes ; Wood, W. Gibson ; Sun, Grace Y. ; Weisman, Gary A. / 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. In: Journal of Neurochemistry. 2009 ; Vol. 109, No. 5. pp. 1300-1310.
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abstract = "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 P2Y 2R was abrogated by pre-incubation with Bay 11-7085, an IκB-α phosphorylation inhibitor, which suggests that P2Y 2R 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.",
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AU - Baker, Olga

AU - Stanley, Emily

AU - Camden, Jean

AU - Seye, Cheikh

AU - Erb, Laurie

AU - Simonyi, Agnes

AU - Wood, W. Gibson

AU - Sun, Grace Y.

AU - Weisman, Gary A.

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AB - 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 P2Y 2R was abrogated by pre-incubation with Bay 11-7085, an IκB-α phosphorylation inhibitor, which suggests that P2Y 2R 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.

KW - Alzheimer's disease

KW - Amyloid precursor protein

KW - P2Y

KW - Primary neuron

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