title: PKR, the double stranded RNA-dependent protein kinase as a critical target in Alzheimer's disease.
abstract: Amyloid beta-peptide (Abeta) deposits and neurofibrillary tangles are key hallmarks in Alzheimer's disease (AD). Abeta stimulates many signal transducers involved in the neuronal death. However, many mechanisms remain to be elucidated because no definitive therapy of AD exists. Some studies have focused on the control of translation which involves eIF2 and eIF4E, main eukaryotic factors of initiation. The availability of these factors depends on the activation of the double-stranded RNA-dependent protein kinase (PKR) and the mammalian target of rapamycin (mTOR), respectively. mTOR positively regulates the translation while PKR results in a protein synthesis shutdown. Many studies demonstrated that the PKR signalling pathway is up-regulated in cellular and animal models of AD and in the brain of AD patients. Interestingly, our results showed that phosphorylated PKR and eIF2alpha levels were significantly increased in lymphocytes of AD patients. These modifications were significantly correlated with cognitive and memory test scores performed in AD patients. On the contrary, the mTOR signalling pathway is down-regulated in cellular and animal models of AD. Recently, we showed that p53, regulated protein in development and DNA damage response 1 and tuberous sclerosis complex 2 could represent molecular links between PKR and mTOR signalling pathways. PKR could be an early biomarker of the neuronal death and a critical target for a therapeutic programme in AD.
authors: Research Group on Brain Aging (EA 3808) University of Poitiers, Poitiers Cedex, France.
authors: Milena
authors: M
authors: Morel
authors: Julien
authors: J
authors: Couturier
authors: Claire
authors: C
authors: Lafay-Chebassier
authors: Marc
authors: M
authors: Paccalin
authors: Guylène
authors: G
authors: Page
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis / Q000201:enzymology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D019892:eIF-2 Kinase