Role of PKR in neuronal death in Alzheimer’s disease.
(2008) 4th Meeting on Brain Aging — Location: Poitiers (14.March.2008)
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- Introduction: It is well known that 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. Among its downstream targets, the Fas-Associated protein with a Death Domain (FADD) and subsequent caspase-8 are responsible for PKR-induced apoptosis in cells infected with virus. However, the role of PKR in DD receptor signaling in AD remains unknown. This project proposes to determine physical and functional interactions of PKR with FAD D in A b neurotoxicity and in APP SLPS1 KI transgenic mice. Methods: Differentiated human (SH-SY5Y) neuroblastoma cells were incubated with 20 µM amyloid-β peptide 1-42 (A b 1–42). After PKR inhibition, death signaling markers were analyzed in nuclear extracts and cellular lysates by western blotting and immucytofluorescence. Three and six month-old APP SL/PS1 KI mice were also examined and compared to control littermates. Results: Immunoblots revealed an increase of TNFα (+406%) and FasL (+255%) levels in hippocampus of APP SLPS1 KI mice at 6 M. PKR and FADD co-immunoprecipitated in cortical mouse homogenates. In SH-SY5Y cells, Phospho-PKR and Phospho-FADD levels increased significantly after 4 hours Ab 1-42 (+126% and +299%, respectively). Physical interaction was observed by confocal staining and confirmed by immunoprecipitation. Treatment with oxindol C16 prevents nuclear Phospho-PKR (-62%) and Phospho-FADD (-45%) expression, and inhibits totally caspase- 8 and -3 activities. Conclusions: These results show the PKR involvement in FADD/cas-pase-8 signaling pathway and underline PKR as a critical target in neuroprotective strategies in AD.
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Couturier, J. (2008). Role of PKR in neuronal death in Alzheimer’s disease. https://hdl.handle.net/2078.5/49359