TY - JOUR T1 - A novel selective PKR inhibitor restores cognitive deficits and neurodegeneration in Alzheimer's disease experimental model JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.121.000590 SP - JPET-AR-2021-000590 AU - Matilde Lopez-Grancha AU - Patrick Bernardelli AU - Nicolas Moindrot AU - Elisabeth Genet AU - Carine Vincent AU - Valerie Roudieres AU - Alain Krick AU - Jean-Francois Sabuco AU - David Machnik AU - Delphine Ibghi AU - Laurent Pradier AU - Veronique Taupin Y1 - 2021/01/01 UR - http://jpet.aspetjournals.org/content/early/2021/06/16/jpet.121.000590.abstract N2 - In Alzheimer's disease (AD), the double-strand RNA-dependent kinase PKR/EIF2AK2 is activated in brain with increased phosphorylation of its substrate eukaryotic initiation factor 2α (eIF2α). AD risk-promoting factors, such as ApoE4 allele or the accumulation of neurotoxic amyloid-beta oligomers (AβO), have been associated with activation of PKR-dependent signalling. Here, we report the discovery of a novel potent and selective PKR inhibitor (SAR439883) and demonstrate its neuroprotective pharmacological activity in AD experimental models. In ApoE4 human replacement male mice, one-week oral treatment with SAR439883 rescued short-term memory impairment in the spatial object recognition test and dose-dependently reduced learning and memory deficits in the Barnes maze test. Moreover, in AβO-injected male mice, a two-week administration of SAR439883 in diet dose-dependently ameliorated the AβO-induced cognitive impairment in both Y-maze and Morris Water Maze, prevented loss of synaptic proteins and reduced levels of the pro-inflammatory cytokine IL-1β. In both mouse models, these effects were associated with a dose-dependent inhibition of brain PKR activity as measured by both PKR occupancy and partial lowering of peIF2α levels. Our results provide evidence that selective pharmacological inhibition of PKR by a small selective molecule can rescue memory deficits and prevent neurodegeneration in animal models of AD-like pathology suggesting that inhibition of PKR is a potential therapeutic approach for AD. Significance Statement We report the identification of a new small molecule potent and selective PKR inhibitor that can prevent cognitive deficits and neurodegeneration in Alzheimer’s disease (AD) experimental models including a mouse model expressing the most prevalent AD genetic risk factor ApoE4. With high potency and selectivity, this PKR inhibitor represents a unique tool for investigating the physiological role of PKR and a starting point for developing new drug candidates for AD. ER -