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Interleukin‐1β enhances nucleotide‐induced and α‐secretase‐dependent amyloid precursor protein processing in rat primary cortical neurons via up‐regulation of the P2Y 2 receptor
Author(s) -
Kong Qiongman,
Peterson Troy S.,
Baker Olga,
Stanley Emily,
Camden Jean,
Seye Cheikh I.,
Erb Laurie,
Simonyi Agnes,
Wood W. Gibson,
Sun Grace Y.,
Weisman Gary A.
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06048.x
Subject(s) - p2y receptor , microbiology and biotechnology , biology , kinase , amyloid precursor protein , protein kinase a , extracellular , receptor , biochemistry , purinergic receptor , medicine , alzheimer's disease , disease
The heterologous expression and activation of the human P2Y 2 nucleotide receptor (P2Y 2 R) 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 P2Y 2 R‐mediated production of sAPPα 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‐1β (IL‐1β) 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 IκB‐α phosphorylation inhibitor, which suggests that P2Y 2 R mRNA transcript levels are regulated through nuclear factor‐κ‐B (NFκB) signaling. Furthermore, the P2Y 2 R agonist Uridine‐5′‐triphosphate (UTP) enhanced the release of sAPPα in rPCNs treated with IL‐1β or transfected with P2Y 2 R 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 P2Y 2 R‐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 P2Y 2 R in neurons.