The PKR activator PACT is induced by Aβ: involvement in Alzheimer's disease

Brain Pathol. 2012 Mar;22(2):219-29. doi: 10.1111/j.1750-3639.2011.00520.x. Epub 2011 Sep 16.


The neuropathological hallmarks of Alzheimer's disease (AD) include senile plaques made of Aβ peptide, neurofibrillary tangles containing hyperphosphorylated tau protein and neuronal loss. The pro-apoptotic kinase PKR can be activated by Aβ and can phosphorylate tau protein via GSK3β kinase activation. The activated form of PKR (pPKR) accumulates in affected neurons and could participate in neuronal degeneration in AD. The mechanism of abnormal PKR activation in AD is not elucidated but could be linked to the PKR activator PACT. PACT stainings, and levels were assessed in the brains of AD patients and in APP/PS1 knock-in transgenic mice and in cell cultures exposed to stresses. We showed that PACT and pPKR colocalizations are enhanced in AD brains. Their levels are increased and correlated in AD and APP/PS1 knock-in mice brains. In human neuroblastoma cells exposed to Aβ, tunicamycin or H2O2, PACT and pPKR concentrations are increased. PACT then PKR inhibitions indicate that PACT is upstream of PKR activation. Our findings demonstrate that PACT levels are enhanced in AD brains and could partly be caused by the action of Aβ. In addition, PACT participates in PKR activation. The PACT-PKR pathway represents a potential link between Aβ accumulation, PKR activation and tau phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / enzymology
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / physiology*
  • Amyloid beta-Peptides / toxicity
  • Animals
  • Cell Line, Tumor
  • Enzyme Induction / physiology
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Phosphorylation
  • RNA-Binding Proteins / biosynthesis*
  • RNA-Binding Proteins / genetics
  • eIF-2 Kinase / metabolism*
  • tau Proteins / metabolism


  • Amyloid beta-Peptides
  • PRKRA protein, human
  • RNA-Binding Proteins
  • tau Proteins
  • eIF-2 Kinase