TY - JOUR T1 - Antagonists targeting eEF2 kinase rescue multiple aspects of pathophysiology in Alzheimer’s disease model mice JF - bioRxiv DO - 10.1101/2021.07.15.452522 SP - 2021.07.15.452522 AU - Nicole P Kasica AU - Xueyan Zhou AU - Xin Wang AU - Wenzhong Yang AU - Helena R Zimmermann AU - Caroline E Holland AU - Elizabeth Koscielniak AU - Hanzhi Wu AU - Anderson O Cox AU - Jingyun Lee AU - Alexey G Ryazanov AU - Cristina M. Furdui AU - Tao Ma Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/07/15/2021.07.15.452522.abstract N2 - It is imperative to develop novel therapeutic strategies for Alzheimer’s disease (AD) and related dementia syndromes based on solid mechanistic studies. Maintenance of memory and synaptic plasticity relies on de novo protein synthesis, which is partially regulated by phosphorylation of eukaryotic elongation factor 2 (eEF2) via its kinase eEF2K. Abnormally increased eEF2 phosphorylation and impaired mRNA translation have been linked to AD. We recently reported that prenatal genetic suppression of eEF2K is able to prevent aging-related cognitive deficits in AD model mice, suggesting the therapeutic potential of targeting eEF2K/eEF2 signaling in AD. Here, we tested two structurally distinct small-molecule eEF2K inhibitors in two different lines of AD model mice after onset of cognitive impairments. Our data revealed that treatment with eEF2K inhibitors improved AD-associated synaptic plasticity impairments and cognitive dysfunction, without altering brain amyloid β (Aβ) and tau pathology. Furthermore, eEF2K inhibition alleviated AD-associated defects in dendritic spine morphology, postsynaptic density formation, protein synthesis, and dendritic polyribosome assembly. Our results may offer critical therapeutic implications for AD, and the proof-of-principle study indicates translational implication of inhibiting eEF2K for AD and related dementia syndromes.One Sentence Summary Treatment with eEF2K inhibitors and genetic eEF2K knockout improved cognitive deficits in Alzheimer’s disease model mice.Competing Interest StatementThe authors have declared no competing interest. ER -