Prolonged Alzheimer-like tau hyperphosphorylation induced by simultaneous inhibition of phosphoinositol-3 kinase and protein kinase C in N2a cells

Guo Gang Xu, Yan Qiu Deng, Shi Jie Liu, Hong Lian Li, Jian Zhi Wang

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18 Citations (Scopus)

Abstract

Co-injection of wortmannin (inhibitor of phosphatidylinositol-3 kinase, PI3K) and GF109203X (inhibitor of protein kinase C, PKC) into the rat brain was found to induce spatial memory deficiency and enhance tau hyperphosphorylation in the hippocampus of rat brain. To establish a cell model with durative Alzheimer-like tau hyperphosphorylation in this study, we treated N2a neuroblastoma cells with wortmannin and GF109203X separately and simultaneously, and measured the glycogen synthase kinase 3 (GSK-3) activity by γ- 32P-labeling and the level of tau phosphorylation by Western blotting. It was found that the application of wortmannin alone only transitorily increased the activity of GSK-3 (about 1 h) and the level of tau hyperphosphorylation at Ser396/Ser404 and Ser 199/Ser202 sites (no longer than 3 h); however, a prolonged and intense activation of GSK-3 (over 12 h) and enhanced tau hyperphosphorylation (about 24 h) were observed when these two selective kinase inhibitors were applied together. We conclude that the simultaneous inhibition of PI3K and PKC can induce GSK-3 overactivation, and further strengthen and prolong the Alzheimer-like tau hyperphosphorylation in N2a cells, suggesting the establishment of a cell model with early pathological events of Alzheimer's disease.

Original languageEnglish
Pages (from-to)349-354
Number of pages6
JournalActa Biochimica et Biophysica Sinica
Volume37
Issue number5
DOIs
Publication statusPublished - 1 May 2005
Externally publishedYes

Keywords

  • Alzheimer's disease (AD)
  • Glycogen synthase kinase 3 (GSK-3)
  • N2a cells
  • Phosphatidylinositol-3 kinase (PI3K)
  • Protein kinase C (PKC)
  • Tau

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