P2Y2 nucleotide receptors enhance α-secretase-dependent amyloid precursor protein processing

Jean M. Camden, Ann M. Schrader, Ryan E. Camden, Fernando A. González, Laurie Erb, Cheikh I. Seye, Gary A. Weisman

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100 Scopus citations


The amyloid precursor protein (APP) is proteolytically processed by β- and γ-secretases to release amyloid β, the main component in senile plaques found in the brains of patients with Alzheimer disease. Alternatively, APP can be cleaved within the amyloid β domain by α-secretase releasing the non-amyloidogenic product sAPPα, which has been shown to have neuroprotective properties. Several G protein-coupled receptors are known to activate α-secretase-dependent processing of APP; however, the role of G protein-coupled nucleotide receptors in APP processing has not been investigated. Here it is demonstrated that activation of the G protein-coupled P2Y2 receptor (P2Y2R) subtype expressed in human 1321N1 astrocytoma cells enhanced the release of sAPPα in a time- and dose-dependent manner. P2Y2R-mediated sAPPα release was dependent on extracellular calcium but was not affected by 1,2-bis(2- aminophenosy)ethane-N,N,N,-trimethylammonium salt, an intracellular calcium chelator, indicating that P2Y2R-stimulated intracellular calcium mobilization was not involved. Inhibition of protein kinase C (PKC) with GF109203 or by PKC down-regulation with phorbol ester pre-treatment had no effect on UTP-stimulated sAPPα release, indicating a PKC-independent mechanism. U0126, an inhibitor of the mitogen-activated protein kinase pathway, partially inhibited sAPPα release by UTP, whereas inhibitors of Src-dependent epidermal growth factor receptor transactivation by P2Y 2Rs had no effect. The metalloprotease inhibitors phenanthroline and TAPI-2 and the furin inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethylketone also diminished UTP-induced sAPPα release. Furthermore, small interfering RNA silencing of an endogenous adamalysin, ADAM10 or ADAM17/TACE, partially suppressed P2Y2R-activated sAPPα release, whereas treatment of cells with both ADAM10 and ADAM17/TACE small interfering RNAs completely abolished UTP-activated sAPPα release. These results may contribute to an understanding of the non-amyloidogenic processing of APP.

Original languageEnglish (US)
Pages (from-to)18696-18702
Number of pages7
JournalJournal of Biological Chemistry
Issue number19
StatePublished - May 13 2005
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Camden, J. M., Schrader, A. M., Camden, R. E., González, F. A., Erb, L., Seye, C. I., & Weisman, G. A. (2005). P2Y2 nucleotide receptors enhance α-secretase-dependent amyloid precursor protein processing. Journal of Biological Chemistry, 280(19), 18696-18702. https://doi.org/10.1074/jbc.M500219200