Modulation of tau phosphorylation by the kinase PKR: implications in Alzheimer's disease

Brain Pathol. 2011 Mar;21(2):189-200. doi: 10.1111/j.1750-3639.2010.00437.x. Epub 2010 Oct 3.


Double-stranded RNA dependent kinase (PKR) is a pro-apoptotic kinase that controls protein translation. Previous studies revealed that activated PKR is increased in brains with Alzheimer's disease (AD). Glycogen Synthase Kinase Aβ (GSK-3β) is responsible for tau phosphorylation and controls several cellular functions also including apoptosis. The goal of this work was to determine if PKR could concurrently trigger GSK-3β activation, tau phosphorylation and apoptosis. In AD brains, both activated kinases co-localize with phosphorylated tau in neurons. In SH-SY5Y cell cultures, tunicamycin and Aβ(1-42) activate PKR, GSK-3β and induce tau phosphorylation and all these processes are attenuated by PKR inhibitors or PKR siRNA. Our results demonstrate that neuronal PKR co-localizes with GSK-3β and tau in AD brains and is able to modulate GSK-3β activation, tau phosphorylation and apoptosis in neuroblastoma cells exposed to tunicamycin or Aβ. PKR could represent a crucial signaling point relaying stress signals to neuronal pathways leading to cellular degeneration in AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Blotting, Western
  • Brain / drug effects
  • Brain / metabolism*
  • Brain / pathology
  • Cell Line
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Fluorescent Antibody Technique
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Immunohistochemistry
  • Microscopy, Confocal
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / pathology
  • Phosphorylation
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • eIF-2 Kinase / metabolism*
  • tau Proteins / drug effects
  • tau Proteins / metabolism*


  • Enzyme Inhibitors
  • tau Proteins
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • eIF-2 Kinase
  • Glycogen Synthase Kinase 3