Memory Center and Department of Biochemistry Lariboisiere Hospital APHP, University Paris
Title: INVOLVEMENT OF PKR IN ALZHEIMER’S DISEASE
Jacques Hugon Professor MD PhD Neurologist at Lariboisiere Hospital Centre Memoir (CMRR) at University of Paris. Chair, Professor, Head of the Department at University of Hong Kong. A team from Lariboisiere Hospital, led by Pr Hugon in Paris France has just revealed that a potent killer enzyme, PKR, was activated in the brain and cerebrospinal fluid (CSF) of AD patients. This team has found that the level of activated PKR was three time higher in the CSF of AD patients as compared to controls. New researches are underway to attenuate its functions by new specific “kinase inhibitors” that could represent a powerful way to attenuate memory deficits in AD patients.
Alzheimer’s disease (AD), is neuropathologically characterized by senile plaques made sof Aβ 1-42 peptide, neurofibrillary tangles composed by hyperphosphorylated tau protein and synaptic and neuronal losses. Aβ 1-42 is known to induce neuronal death. PKR is a pro-apoptotic kinase that can phosphorylate the initiation factor eIF2α and reduce protein translation. The activation of PKR is induced by virus, cytokines, calcium, and Aβ 1-42. PKR can also modulate inflammation and the genetic knock down of PKR improves memory in experimental mice. Our group has been working on PKR for the last years and we have shown that activated PKR accumulates in the degenerating neurons of AD patients and that PKR can experimentally control the expression of the APP cleaving enzyme BACE1, reduce the production of Aβ peptide and indirectly induce in neuronal cell cultures the phosphorylation of tau protein In a recent study we have analyzed CSF levels of PKR and activated PKR (pPKR) in AD patients compared to neurological controls and patients with amnestic Mild Cognitive Impairment (MCI). The CSF of 45 AD patients, 11 patients with Mild Cognitive Impairment and 35 neurological controls were assessed and the patients were followed for more than 2 years. CSF levels of Aβ 1-42, Tau, pTau, PKR and pPKR were evaluated. Cognitive assessments were carried out twice a year. All patients or care givers gave their written inform consents. The mean CSF pPKR level was increased (300%) in AD patients compared to neurological disease controls. The sensitivity was 91.1% and the specificity was 94.3%. Many MCI patients had also increased pPKR concentrations. In AD patients PKR and pPKR levels correlate with pTau levels and with the cognitive decline assessed by MMSE over more than 2 years. In conclusion, experimental and clinical data suggests that pPKR is detrimental to the formation of memory and that this activated kinase interferes with the abnormal molecular pathways and the clinical evolution of the disease. PKR represents a possible new biomarker and pharmacological target in AD.
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