Modulation of Tau Phosphorylation by the Kinase PKR: Implications in Alzheimer's Disease

• Published in: Brain pathology (Zurich, Switzerland) Vol. 21; no. 2; pp. 189 - 200
• Main Authors: Bose, Anindita, Mouton-Liger, François, Paquet, Claire, Mazot, Pierre, Vigny, Marc, Gray, Françoise, Hugon, Jacques
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.03.2011
• Subjects: Alzheimer; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Blotting, Western; Brain - drug effects; Brain - metabolism; Brain - pathology; Cell Line; eIF-2 Kinase - metabolism; Enzyme Activation - physiology; Enzyme Inhibitors - pharmacology; Fluorescent Antibody Technique; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; GSK-3β; Humans; Immunohistochemistry; Microscopy, Confocal; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Phosphorylation; PKR; Signal Transduction - drug effects; Signal Transduction - physiology; tau protein; tau Proteins - drug effects; tau Proteins - metabolism
• ISSN: 1015-6305; 1750-3639
• DOI: 10.1111/j.1750-3639.2010.00437.x

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 Aβ1‐42 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.