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PKR involvement in Alzheimer’s disease

Abstract : AbstractBackgroundBrain lesions in Alzheimer’s disease (AD) are characterized by Aβ accumulation, neurofibrillary tangles, and synaptic and neuronal vanishing. According to the amyloid cascade hypothesis, Aβ1-42 oligomers could trigger a neurotoxic cascade with kinase activation that leads to tau phosphorylation and neurodegeneration. Detrimental pathways that are associated with kinase activation could also be linked to the triggering of direct neuronal death, the production of free radicals, and neuroinflammation.ResultsAmong these kinases, PKR (eukaryotic initiation factor 2α kinase 2) is a pro-apoptotic enzyme that inhibits translation and that has been implicated in several molecular pathways that lead to AD brain lesions and disturbed memory formation. PKR accumulates in degenerating neurons and is activated by Aβ1-42 neurotoxicity. It might modulate Aβ synthesis through BACE 1 induction. PKR is increased in cerebrospinal fluid from patients with AD and mild cognitive impairment and can induce the activation of pro-inflammatory pathways leading to TNFα and IL1-β production. In addition, experimentally, PKR seems to down-regulate the molecular processes of memory consolidation. This review highlights the major findings linking PKR and abnormal brain metabolism associated with AD lesions.ConclusionsStudying the detrimental role of PKR signaling in AD could pave the way for a neuroprotective strategy in which PKR inhibition could reduce neuronal demise and alleviate cognitive decline as well as the cumbersome burden of AD for patients.
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Jacques Hugon, François Mouton-Liger, Julien Dumurgier, Claire Paquet. PKR involvement in Alzheimer’s disease. Alzheimer's Research and Therapy, BioMed Central, 2016, 9 (1), pp.83. ⟨10.1186/s13195-017-0308-0⟩. ⟨inserm-01612743⟩



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