Abstracts

Alzheimer’s disease (AD), the most common form of dementia in the elderly, is amultifactoral pathology leading to a progressive deterioration of cognitivefunctions with loss of memory. Previous studies demonstrated that the PKR(double-stranded RNA-activated Protein Kinase) signalling pathway, activated by awide range of stimuli including the Ab-peptide, contributed to neurodegenerationin AD. Moreover, pharmacological inhibition of this kinase with a specificinhibitor, the C16 compound, prevents the Ab-induced toxicity in humanSH-SY5Y neuroblastoma cell line and rat primary neuronal culture. This studyinvestigates the mnesic disturbances of both long- and short-term memories in theAPPswePS1dE9 mouse model for AD and the potential in vivo effects of apharmacological inhibition of PKR with the C16 compound.Female APPswePS1dE9 mice, aged 3 months, received a chronic intraperitonealinjection of C16 at a dose of 0.5 mg/kg every 3 days. Wild-type (WT) littermateswere used as controls. Memory function was evaluated in the morris-water-mazeand Y-maze tests.In the water-maze task, the distance covered to find the platform in the North Eastquadrant decreased over the course of acquisition training for the control micewhatever the age, with a diminution of distance travelled between trial 1 and trial4. For the APPswePS1dE9 group, the same significant decrease in distance coveredwas observed at 6 and 9 months of age but not at 12 and 18. During the probe test,performed 24 h after the last training session, significant differences were observedbetween all groups in their distance covered in target quadrant with AP-PswePS1dE9 mice travelling shorter distance in this quadrant than WT from theage of 9 months. Concerning Y-Maze test, APPswePS1dE9 mice displayed asignificant impairment in their spontaneous alternation behaviour at 12 and18 months of age compared to WT, without modification of explorative behaviour.In light of these results, the age of 12 months was chosen to evaluate the effect ofC16 compound on these alterations. Unfortunately, C16 did not prevent deficits inlearning and memory at 12 and 18 months of age and did not reverse thealterations of alternation performances in Y-Maze test. In parallel to behaviouralanalysis, biochemical parameters were investigated in brain homogenates of thesemice and results showed that pharmacological inhibition of PKR failed to prevent inflammation and led to an increase in amyloid levels at 18 months of age, datathat question the strategies targeting PKR as neuroprotective in AD