Memory impairments and synaptic deficits in Tg19959 and APP/PS1 AD model mice are alleviated by eEF2K inhibitor A‐484954

Abstract

AbstractBackgroundMounting evidence indicates synaptic failure as an early and key event in Alzheimer’s Disease (AD) pathophysiology. Maintenance of long‐term memory and synaptic plasticity requires de novo protein synthesis. Phosphorylation of mRNA translation factor eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K results in inhibition of general protein synthesis. Previous studies have shown elevated levels of eEF2 phosphorylation in post mortem AD human brain tissue and in AD mouse models. Here, we investigated whether suppression of eEF2 phosphorylation via eEF2K inhibitor A‐484954 can alleviate AD‐associated synaptic failure and memory impairments.MethodAged Tg19959 mice (6‐9 months), APP/PS1 (12‐16 months) and age‐matched controls were treated with a subcutaneous pellet containing A‐484954 or vehicle. The pellet continuously releases treatment over 30 days. Starting two weeks after pellet placement, the mice underwent cognitive assessment via the Novel Object Recognition (NOR) and Morris Water Maze (MWM) tasks. Golgi‐Cox Stain, Amyloid Beta immunohistochemistry, Western blots, SUnSET Assays, mass spectrometry (MS) proteomic analysis, and transmission electron microscopy (TEM) were also performed.ResultWe found that cognitive impairments displayed in aged Tg19959 and APP/PS1 mice were alleviated with treatment of A‐484954. Brain tissue from these mice also underwent high performance liquid chromatography (HPLC) to assess drug concentration in the brain. In addition, Golgi‐Cox stain was done to assess dendritic spine density and morphology. Spine analysis indicates a rescue in levels of mature spines in the CA1 region of the hippocampus in APP/PS1 mice treated with A‐484954. TEM analysis indicated a rescue in dendritic polyribosome assembly, post‐synaptic density (PSD) formation, and PSD length. Additionally, SUnSET assays revealed a rescue in translational capacity in the hippocampi of AD mice treated with A‐484954.ConclusionTaken together, our results suggest that treatment with a eEF2K inhibitor, A‐484954, alleviates cognitive impairments, restores synaptic morphology, and rescues translational capacity in mouse models of AD.