PKR involvement in Alzheimer’s disease

Abstract

BackgroundBrain 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.

PKR knockout in the 5xFAD model of Alzheimer's disease reveals beneficial effects on spatial memory and brain lesions

“…One such kinase is protein kinase R (PKR), a ubiquitous pro‐apoptotic serine/threonine kinase that participates in the “integrated stress response” (ISR)(Marchal et al, ) (Patel & Sen, ) (Shimazawa, Ito, Inokuchi, & Hara, ) (Harding et al, ), a cell stress response key to cell homeostasis. PKR is activated in AD brains (Chang, Suen, et al, ; Chang, Wong, Ng, & Hugon, ; Hugon, Mouton‐Liger, Dumurgier, & Paquet, ; Page et al, ; Paquet et al, ), and its concentration in the cerebrospinal fluid (CSF) predicts cognitive decline (Dumurgier et al, ; Mouton‐Liger, Paquet, Dumurgier, Lapalus, et al, ). PKR activation can control tau phosphorylation (Bose et al, ; Suen, Yu, So, Chang, & Hugon, ), the expression of the Aβ‐forming protein BACE1 (Ill‐Raga et al, ; Mouton‐Liger, Paquet, Dumurgier, Bouras, et al, ), and neuroinflammation linked to innate immunity (Kang & Tang, ).…”

“…PKR activation can control tau phosphorylation (Bose et al, ; Suen, Yu, So, Chang, & Hugon, ), the expression of the Aβ‐forming protein BACE1 (Ill‐Raga et al, ; Mouton‐Liger, Paquet, Dumurgier, Bouras, et al, ), and neuroinflammation linked to innate immunity (Kang & Tang, ). More information can be found in a recent review on PKR and AD (Hugon et al, ). PKR impairs memory formation in mice (Zhu et al, ).…”

Acteoside Attenuates Oxidative Stress and Neuronal Apoptosis in Rats with Focal Cerebral Ischemia–Reperfusion Injury

“…9) Besides, ACT mitigated amyloid β peptide-induced cognitive dysfunction, neurotoxicity, and neurochemical disturbances via reducing amyloid protein deposition. 10) However, whether ACT exerts its neuroprotective effect in cerebral I/R injury remains elusive.…”

A truncated PACT protein resulting from a frameshift mutation reported in movement disorder DYT16 triggers caspase activation and apoptosis

“…A significant amount of evidence exists to indicate a possible connection between PACT and PKR recruitment to such aggregates. A number of studies have implicated PKR in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) . Of these, PKR activation has been most investigated in Alzheimer's disease.…”