PKR involvement in Alzheimer's disease

Background: Brain lesions in Alzheimer's disease (AD) are characterized by A beta accumulation, neurofibrillary tangles, and synaptic and neuronal vanishing. According to the amyloid cascade hypothesis, A beta 1-42 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. Results: Among these kinases, PKR (eukaryotic initiation factor 2 alpha 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 A beta 1-42 neurotoxicity. It might modulate A beta 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 TNF alpha and IL1-beta 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. Conclusions: Studying 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.