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Review
. 2017 Oct 5;9(1):83.
doi: 10.1186/s13195-017-0308-0.

PKR involvement in Alzheimer's disease

Jacques Hugon  1   2 , François Mouton-Liger  3 , Julien Dumurgier  4 , Claire Paquet  4
Affiliations
Review

PKR involvement in Alzheimer's disease

Jacques Hugon et al. Alzheimers Res Ther. .

Abstract

Background: Brain 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.

Results: Among 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.

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.

Keywords: Alzheimer’s disease; Amyloid; Apoptosis; Biomarkers; Kinases; Neurons; PKR; Therapeutics.

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Conflict of interest statement

Consent for publication

Not applicable.

Competing interests

JH, JD, and CP are investigators in studies sponsored by Eli Lilly, Roche, Xigen, Lundbeck, Biogen, Axovant, Eisai, Piramal, and Raman. JH has been a consultant for Roche, Eli Lilly, Novartis, Lundbeck, and Raman. CP has been a consultant for Eli Lilly. FML has nothing to declare.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
The possible signaling stress pathways contributing to the integrated stress response and PKR activation in neurodegenerative diseases, as well as the molecular consequences of PKR activation in AD, Parkinson’s disease (PD) and Huntington’s disease (HD)
Fig. 2
Fig. 2
Phosphorylated PKR immunostaining in AD and control brains. a AD brain PKR staining is localized to neuritic dendrites surrounding an amyloid plaque, as well as in the cytosol of neighboring neurons (bar = 60 μm). The arrow indicates dystrophic neurites positive for pPKR staining. b No neuronal staining is depicted in a control brain (bar = 20 μm). c AD brain PKR immunostaining is seen in neuronal cytosolic vacuoles (bar = 20 μm). The arrow indicates pPKR accumulation in neurons from an AD brain. Original figure from authors
See this image and copyright information in PMC

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