Repression of eEF2 kinase improves deficits in novel object recognition memory in aged mice

Gosrani, Saahj P.; Jester, Hannah M.; Zhou, Xueyan; Ryazanov, Alexey G.; Ma, Tao

doi:10.1016/j.neurobiolaging.2020.07.016

Cited by 17 publications

(18 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First, mounting evidence demonstrates that eEF2K activity is not required for development or cell survival under physiological conditions. Mice with global knockout of the eEF2K gene appear normal during different stages of development as demonstrated in multiple studies (Beckelman et al, 2019;Gosrani et al, 2020;Ryazanov, 2002). We also did not observe any adverse effects in WT mice treated with the eEF2K inhibitor AG, including weight changes and gross morphology of hippocampus (Figure S1c,h,i).…”

Section: Discussionsupporting

confidence: 77%

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

Kasica

Zhou

Yang

et al. 2022

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 77%

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

Kasica

Zhou

Yang

et al. 2022

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…First, mounting evidence demonstrates that eEF2K activity is not required for development or cell survival under physiological conditions. Mice with global knockout of the eEF2K gene appear normal during different stages of development as demonstrated in multiple studies (19,41,42). We also did not observe any adverse effects in WT mice treated with the eEF2K inhibitor AG, including weight changes and gross morphology of hippocampus (Fig.…”

Section: Discussionsupporting

confidence: 79%

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

Kasica

Zhou

Wang

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

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 (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.

show abstract

“…6a, b ), suggesting that protein synthesis is required to maintain TyrRS levels under normal conditions. We previously showed that genetic reduction of eEF2K attenuates age-related memory deficits in mice 46 . Consistently, we found that TyrRS and PheRSβ were increased in the brain tissue samples of eEF2K +/− mice (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Cis- and trans-resveratrol have opposite effects on histone serine-ADP-ribosylation and tyrosine induced neurodegeneration

et al. 2022

Self Cite

View full text Add to dashboard Cite

Serum tyrosine levels increase during aging, neurocognitive, metabolic, and cardiovascular disorders. However, calorie restriction (CR) and sleep lower serum tyrosine levels. We previously showed that tyrosine inhibits tyrosyl-tRNA synthetase (TyrRS)-mediated activation of poly-ADP-ribose polymerase 1 (PARP1). Here, we show that histone serine-ADP-ribosylation is decreased in Alzheimer’s Disease (AD) brains, and increased tyrosine levels deplete TyrRS and cause neuronal DNA damage. However, dopamine and brain-derived neurotrophic factor (BDNF) increase TyrRS and histone serine-ADP-ribosylation. Furthermore, cis-resveratrol (cis-RSV) that binds to TyrRS mimicking a ‘tyrosine-free’ conformation increases TyrRS, facilitates histone serine-ADP-ribosylation-dependent DNA repair, and provides neuroprotection in a TyrRS-dependent manner. Conversely, trans-RSV that binds to TyrRS mimicking a ‘tyrosine-like’ conformation decreases TyrRS, inhibits serine-ADP-ribosylation-dependent DNA repair, and induces neurodegeneration in rat cortical neurons. Our findings suggest that age-associated increase in serum tyrosine levels may effect neurocognitive and metabolic disorders and offer a plausible explanation for divergent results obtained in clinical trials using resveratrol.

show abstract

Repression of eEF2 kinase improves deficits in novel object recognition memory in aged mice

Cited by 17 publications

References 28 publications

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

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

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

Cis- and trans-resveratrol have opposite effects on histone serine-ADP-ribosylation and tyrosine induced neurodegeneration

Contact Info

Product

Resources

About