Antagonists targeting eEF2 kinase rescue multiple aspects of pathophysiology in Alzheimer’s disease model mice

• Published in: Journal of neurochemistry Vol. 160; no. 5; pp. 524 - 539
• Main Authors: Kasica, Nicole P., Zhou, Xueyan, Yang, Qian, Wang, Xin, Yang, Wenzhong, Zimmermann, Helena R., Holland, Caroline E., Koscielniak, Elizabeth, Wu, Hanzhi, Cox, Anderson O., Lee, Jingyun, Ryazanov, Alexey G., Furdui, Cristina M., Ma, Tao
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.03.2022
• Subjects: Aging; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animal models; Animals; Antagonists; Cognitive ability; Dementia; Dementia disorders; Dendritic spines; Disorders; eEF2K; eEF2K inhibitors; Elongation; Elongation Factor 2 Kinase - genetics; Elongation Factor 2 Kinase - metabolism; Genetic suppression; Inhibitors; Kinases; Mice; mRNA; Neurodegenerative diseases; Peptide Elongation Factor 2 - metabolism; Phosphorylation; Plasticity; Protein biosynthesis; Protein synthesis; Proteins; Spine; synapses; Synaptic density; Synaptic plasticity; Syndrome; Tau protein; eEF2K; protein synthesis; synapses; eEF2K inhibitors; Alzheimer's disease
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15562

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 the 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, post‐synaptic 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. Cover Image for this issue: https://doi.org/10.1111/jnc.15392 a) Alzheimer's disease (AD)‐associated increase in eukaryotic elongation factor 2 kinase (eEF2K) activity hyper‐phosphorylates eukaryotic elongation factor 2 (eEF2). This inhibitory phosphorylation leads to a decrease in de novo protein synthesis, which leads to impaired learning and memory. b) We proposed that treatment with eEF2K inhibitors would decrease AD‐associated hyper‐phosphorylation of eEF2 and subsequent dysregulation of protein synthesis and cognitive deficits in transgenic AD model mice. eEF2K inhibitors A‐484954 and NH125 rescued cognitive deficits, translational capacity, and synaptic function in AD model mice. These findings suggest that antagonists of eEF2K may be a novel therapeutic approach for AD. Cover Image for this issue: https://doi.org/10.1111/jnc.15392