The double-stranded RNA-dependent Protein Kinase controls the production and release of tumor necrosis factor alpha in amyloid neurotoxicity and in lymphocytes of patients with Alzheimer’s disease.

Couturier, Julien;Chalon, Sylvie;Moreau, Cynthia;Pontcharraud, Raymond;Page, Guylène;et.al.
(2009) 9e Colloque de la Société des Neurosciences — Location: Bordeaux (26.May.2009)

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  • Couturier, JulienUCLouvain
    Author
  • Chalon, SylvieUniversité de Tours
    Collaborator
  • Moreau, CynthiaUniversité de Poitiers
    Collaborator
  • Pontcharraud, RaymondUniversité de Poitiers
    Collaborator
  • Page, GuylèneUniversité de Poitiers
    Scientific Director/Editor
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Abstract
It is well known that the double-stranded RNA-dependent Protein Kinase (PKR) is not only activated in various models of Alzheimer's disease (AD) and in AD patients but also associated with neurodegeneration and cognitive decline observed in this dementia. Recent studies reported that PKR could be involved in the control of inflammatory factors expression, including (TNFalpha). This study aims to investigate the effects of the PKR pharmacological inhibition on the production and the release of TNFalpha in a mouse Amyloid Beta (Abeta42) -treated co-culture containing physiological proportions of neurons (45%), astrocytes (40%) and microglia (15%), and also to test the specific PKR inhibitor on human lymphocytes of AD patients. Quantification of TNFalpha by ELISA in a mouse co-culture model showed a significant increase of its intracellular and extracellular levels after 72h and 96h of treatment with 20 microM Abeta42. This TNFalpha production was associated with an increase of the caspase-3 activation, known to be involved in the induction of apoptosis in AD. Treatment with a specific inhibitor of PKR (C16 compound) prevented not only the increase of TNFalpha expression and release after 72h of intoxication with Abeta42, but also the caspase-3 activation in this cellular model. Preliminary results obtained with the PKR inhibitor treatment on human AD lymphocytes in culture showed a significant decrease in the PKR expression inducing a breakdown in the TNFalpha production and release. These results are consistent with the fact that a decrease of PKR activation could participate to a decrease in the massive inflammatory process observed in AD and partly responsible for the induction of the death message leading to the neuronal loss.
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Couturier, J. (2009). The double-stranded RNA-dependent Protein Kinase controls the production and release of tumor necrosis factor alpha in amyloid neurotoxicity and in lymphocytes of patients with Alzheimer’s disease. https://hdl.handle.net/2078.5/99675