The kinase PKR: A diagnostic and therapeutic target in Alzheimer's disease

Backgrounds: Alzheimer Disease (AD) is clinically marked by memory disturbances followed by aphasia, apraxia and agnosia with behavioural symptoms. Neurpathological lesions include senile plaques formed by Amyloid peptide Aβ 1-42, neurofibrillary tangles made of hyperphosphorylated tau protein and synaptic and neuronal losses. The cause of AD is unknown but the oligomers of Aβ 1-42 could lead to neurodegeneration. The cerebrospinal fluid (CSF) levels of Aβ 1-42, Tau and phosphorylated tau (pTau) are modified in AD. PKR is a pro-apoptotic kinase that controls protein synthesis. PKR is activated by cytokines, calcium, viruses and Aβ 1-42. The activation of PKR induces inflammation, and modulates the levels of BACE 1 and Aβ 1-42 production as well as the phosphorylation of tau protein. The genetic knock down of PKR improves memory in normal experimental mice. The goal of the present study was to determine if the levels of PKR and activated PKR (pPKR) were increased in the CSF of AD patients compared to neurological controls. Methods: In a prospective cohort analysis, 45 AD patients, 11 patients with Mild Cognitive Impairment (MCI) and 35 neurological control individuals were included in this study. After diagnosis, all patients had a lumbar puncture to determine the CSF levels of Aβ 1-42, Tau and pTau using an ELISA assay (Innogenetics) and the concentrations of PKR and pPKR using western blot procedures. All patients or care giver gave their written inform consents. This study has been approved by the local ethics committee. Results: The mean CSF pPKR level was increased by 300% in AD patients compared to neurological controls. The sensitivity was 91.1% and the specificity was 94.3%. pPKR concentrations were also increased in the majority of MCI patients. In AD patients PKR and pPKR levels correlate with pTau levels. Some AD patients with normal Aβ 1-42, Tau and pTau levels had abnormal pPKR concentrations. Conclusions: The evaluation of CSF PKR and pPKR concentrations could help to improve AD diagnosis and PKR is a new therapeutic target to decrease neurodegeneration and improve memory in AD patients.