Antagonists targeting eEF2 kinase rescue multiple aspects of pathophysiology in Alzheimer’s disease model mice
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Abstract
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. image Cover Image for this issue: https://doi.org/10.1111/jnc.15392
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eEF2K inhibition could stabilize newly potentiated synapses and extend antidepressant duration by sustaining protein synthesis downstream.
“By sustaining protein synthesis downstream, eEF2K inhibition could stabilize newly potentiated synapses and extend antidepressant duration [147,156,158].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [158]
The Discussion says eEF2K inhibition improves overall protein synthesis, and the Results report improved long-term potentiation and synaptic structure in Alzheimer’s model mice. The paper does not establish that inhibition stabilizes newly potentiated synapses or extends antidepressant duration; its findings concern Alzheimer’s-related deficits. (LLM, conf=0.86)
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“13,25,26,57,58 61 Regulation of protein synthesis has been associated with distinct translational factors involved in each phase of mRNA translation.”
BackgroundInfluentialSelf-citationSynaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery
Tanaka, M. (2026) · Biomedicines · doi:10.3390/biomedicines14061265
- Authors
- Kasica, N. P., Zhou, X., Yang, Q., Wang, X., Yang, W., Zimmermann, H. R., Holland, C. E., Koscielniak, E., Wu, H., Cox, A. O., Lee, J., Ryazanov, A. G., Furdui, C. M., & Ma, T.
- Affiliations
- Wake Forest University Health Sciences (US)
- Atrium Health Wake Forest Baptist (US)
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Ma, Tao
- ORCID
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2022-01-04
- Volume
- 160
- Issue
- 5
- Pages
- 524-539
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- PMC
- PMC8902702
- OpenAlex
- W4200005458
- Cited by
- 34
- References
- 51
- Citations by year
- 2026: 9 · 2025: 3 · 2024: 11 · 2023: 10 · 2022: 1
- FWCI
- 4.08
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Journal of Neurochemistry (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01 AG055581, R01 AG056622)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, eEF2K, elongation factor 2, mRNA translation, synaptic plasticity, cognitive impairment, dendritic spine morphology, postsynaptic density, protein synthesis, amyloid-beta, tau pathology, dementia
- MeSH terms
- Alzheimer Disease, Animals, Phosphorylation, Syndrome, Amyloid beta-Peptides, Peptide Elongation Factor 2, Mice, Elongation Factor 2 Kinase
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