Overactivated mitogen-activated protein kinase by anisomycin induces tau hyperphosphorylation

Sheng Li Xue Bao. 2008 Aug 25;60(4):485-91.

Abstract

One of the pathological feathers of Alzheimer's disease (AD) is neurofibrillary tangles (NFTs), which consist of paired helical filaments (PHFs) formed by hyperphosphorylated microtubule-associated protein tau. To study the role of mitogen-activated protein kinase (MAPK) in tau hyperphosphorylation and the underlying mechanism, wild type mouse neuroblastoma cells (N2a) were dealt with different concentrations (0.1 microg/mL, 0.2 microg/mL and 0.4 microg/mL) of anisomycin (an activator of MAPK) for 6 h. The relationship between MAPK activity and tau phosphorylation at some Alzheimer-sites was analyzed, and the activities of protein kinase A (PKA) and glycogen synthase kinase-3 (GSK-3) were detected. The results showed that anisomycin activated MAPK in a dose-dependent manner, but tau hyperphosphorylation at Ser-198/199/202 and Ser-396/404 sites was only observed when the concentration of anisomycin was at the level of 0.4 microg/mL, and the alteration of tau phosphorylation at Ser-214 showed no significant difference in different groups. 0.2 microg/mL and 0.4 microg/mL of anisomycin led to an increase in the activity of GSK-3, respectively, but had no effect on the activity of PKA. Lithium chloride, a specific inhibitor of GSK-3, completely abolished the anisomycin-induced elevation of tau phosphorylation without any effect on the activity of MAPK. In conclusion, overactivation of MAPK up to a certain degree induces tau hyperphosphorylation at Ser-198/199/202 and Ser-396/404 sites, and this is probably related to the effect of activated GSK-3 by MAPK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / pathology
  • Animals
  • Anisomycin / pharmacology*
  • Cell Line, Tumor
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Glycogen Synthase Kinase 3 / metabolism*
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neurofibrillary Tangles / pathology
  • Phosphorylation
  • tau Proteins / metabolism*

Substances

  • tau Proteins
  • Anisomycin
  • Cyclic AMP-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Glycogen Synthase Kinase 3