SELECTIVE PKR INHIBITION RESCUES MEMORY DEFICITS AND NEURODEGENERATION IN MOUSE MODELS WITH PATHOLOGICAL FEATURES OF ALZHEIMER’S DISEASE

The protein kinase R (PKR) is activated in response to stress signals, including those triggered by pathological mechanisms associated with Alzheimer's disease (AD). In AD patients, PKR pathway activation has been observed in the brain with elevated levels of auto-phosphorylated PKR (pPKR) and of its phosphorylated substrate, eukaryotic initiation factor 2α (peIF2α). Higher pPKR levels in AD patient cerebrospinal fluid (CSF) have been correlated with a more rapid cognitive decline. In addition, AD risk-promoting factors, including ApoE4 (i.e. in human carriers and in ApoE4 knock-in mice), or the accumulation of neurotoxic β-amyloid oligomers (AβOs), have been associated with activation of PKR-dependent signaling. The activity of a potent and selective PKR inhibitor (SAR489883) was evaluated after oral treatment in ApoE4 knock-in (KI) mice and in C57Bl/6 mice in which AbOs were administered by intra-cerebroventricular injection. The effects of SAR489883 were characterized on cognitive functions using the Barnes maze test in ApoE4 KI mice and with the Morris water maze test in AβO-injected mice. Effects of SAR489883 on synapse loss were assessed by measuring brain levels of SNAP25, PSD95 and synaptophysin and on a hallmark of neuroinflammation, brain IL1β, using ELISA. PKR activity was also evaluated in these studies by measuring both PKR occupancy, using KiNativTM technology, and brain levels of peIF2α, using semi-automated Western blot. In ApoE4 KI mice, one-week oral BID administration of SAR489883 dose-dependently reduced learning and memory deficits. In AβO-injected mice, a two-week administration of SAR489883 in the diet also dose-dependently reduced cognitive impairment, rescued deficits of synaptic proteins and reduced IL-1b. In both mouse models, these effects were associated with a dose-dependent inhibition of PKR activity in the brain. Our results demonstrate that selective pharmacological inhibition of PKR can rescue memory deficits and block neurodegeneration in animal models of AD-like pathology. These data suggest that the PKR pathway contributes to AD pathogenic mechanisms and that inhibition of PKR has the potential to be used as a disease modifying and symptomatic treatment for AD.