Increased Cerebrospinal Fluid Levels of Double-Stranded RNA-Dependant Protein Kinase in Alzheimer's Disease

Mouton-Liger, François; Paquet, Claire; Dumurgier, Julien; Lapalus, Pauline; Gray, Françoise; Laplanche, Jean-Louis; Hugon, Jacques; Groupe d'Investigation du Liquide Céphalorachidien Study Network,

doi:10.1016/j.biopsych.2011.11.031

« Previous Next »Biological Psychiatry
Volume 71, Issue 9 , Pages 829-835, 1 May 2012

Increased Cerebrospinal Fluid Levels of Double-Stranded RNA-Dependant Protein Kinase in Alzheimer's Disease

François Mouton-Liger
- Memory Clinical Center, Lariboisiere Fernand Widal Saint Louis Hospital, Assistance Publique –Hôpitaux de Paris, University of Paris Diderot, Paris, France
- Institut du Fer à Moulin Inserm UMRS 839, Lariboisiere Fernand Widal Saint Louis Hospital, Assistance Publique –Hôpitaux de Paris, University of Paris Diderot, Paris, France
- Department of Histology, Lariboisiere Fernand Widal Saint Louis Hospital, Assistance Publique –Hôpitaux de Paris, University of Paris Diderot, Paris, France
Claire Paquet
- Memory Clinical Center, Lariboisiere Fernand Widal Saint Louis Hospital, Assistance Publique –Hôpitaux de Paris, University of Paris Diderot, Paris, France
- Institut du Fer à Moulin Inserm UMRS 839, Lariboisiere Fernand Widal Saint Louis Hospital, Assistance Publique –Hôpitaux de Paris, University of Paris Diderot, Paris, France
- Department of Histology, Lariboisiere Fernand Widal Saint Louis Hospital, Assistance Publique –Hôpitaux de Paris, University of Paris Diderot, Paris, France
Julien Dumurgier
- Memory Clinical Center, Lariboisiere Fernand Widal Saint Louis Hospital, Assistance Publique –Hôpitaux de Paris, University of Paris Diderot, Paris, France
Pauline Lapalus
- Memory Clinical Center, Lariboisiere Fernand Widal Saint Louis Hospital, Assistance Publique –Hôpitaux de Paris, University of Paris Diderot, Paris, France
Françoise Gray
- Department of Pathology, Lariboisiere Fernand Widal Saint Louis Hospital, Assistance Publique –Hôpitaux de Paris, University of Paris Diderot, Paris, France
Jean-Louis Laplanche
- Department of Biochemistry, Lariboisiere Fernand Widal Saint Louis Hospital, Assistance Publique –Hôpitaux de Paris, University of Paris Diderot, Paris, France
Jacques Hugon
- Memory Clinical Center, Lariboisiere Fernand Widal Saint Louis Hospital, Assistance Publique –Hôpitaux de Paris, University of Paris Diderot, Paris, France
- Institut du Fer à Moulin Inserm UMRS 839, Lariboisiere Fernand Widal Saint Louis Hospital, Assistance Publique –Hôpitaux de Paris, University of Paris Diderot, Paris, France
- Department of Histology, Lariboisiere Fernand Widal Saint Louis Hospital, Assistance Publique –Hôpitaux de Paris, University of Paris Diderot, Paris, France
- Address correspondence to Jacques Hugon, M.D., Ph.D., Institut du Fer à Moulin Inserm UMRS 839, Memory Clinical Center Paris Nord Ile-de-France, 200 rue du Faubourg Saint-Denis, Paris 75010, France
Groupe d'Investigation du Liquide Céphalorachidien Study Network

Received 8 July 2011; received in revised form 16 November 2011; accepted 16 November 2011. published online 27 January 2012.

Background

The pathological hallmarks of Alzheimer's disease (AD) include accumulation of amyloid-β (Aß) peptide forming extracellular senile plaques, neurofibrillary tangles made of hyperphosphorylated tau protein with neuronal loss. Aβ peptide (1–42), total tau (T-tau), and phosphorylated tau at threonine 181 (p181tau) levels in the cerebrospinal fluid (CSF) are now validated biomarkers. The proapoptotic kinase R (PKR), is activated by Aβ accumulates in degenerating neurons in AD brains and controls protein synthesis and indirectly tau phosphorylation.

Methods

In a prospective cohort study, the CSF of 91 patients were studied (AD: 45; amnestic mild cognitive impairment: 11; neurological disease control subjects [NDC]: 35). The levels of total PKR (T-PKR), phosphorylated PKR (pPKR), Aß 1–42, T-tau, and p181tau were assessed by immunoblotting or enzyme-linked immunosorbent assay methods. Receivers operating characteristic curves were used to examine the discriminatory power of T-PKR, pPKR, and pPKR/T-PKR ratio between AD and NDC patients.

Results

Total PKR and pPKR concentrations were elevated in AD and amnestic mild cognitive impairment subjects. We have determined a pPKR value (optical density units) that could discriminate AD patients from control subjects with a sensitivity of 91.1% and a specificity of 94.3%. Among AD patients, T-PKR and pPKR levels correlate with CSF p181tau levels. Some AD patients with normal CSF Aß, T-tau, or p181tau levels had abnormal T-PKR and pPKR levels.