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Memory impairments in Tg19959 and APP/PS1 AD model mice are alleviated by eEF2K inhibitor A‐484954
Author(s) -
Kasica Nicole P,
Yang Wenzhong,
Zhou Xueyan,
Ma Tao
Publication year - 2021
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.051810
Subject(s) - morris water navigation task , synaptic plasticity , hippocampus , dendritic spine , phosphorylation , immunohistochemistry , pharmacology , medicine , neuroscience , chemistry , biology , microbiology and biotechnology , hippocampal formation , receptor
Background Mounting 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 Method Aged 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, and a variety of other experiments were performed on the mice after sacrifice. Result We 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 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. Conclusion Taken together, our results suggest that treatment with a eEF2K inhibitor, A‐484954, alleviates cognitive impairments and restores synaptic morphology in two mouse models of AD.