Genetic reduction of eEF2 kinase alleviates pathophysiology in Alzheimer’s disease model mice
Brenna C. Beckelman, … , Alexey G. Ryazanov, Tao Ma
Brenna C. Beckelman, … , Alexey G. Ryazanov, Tao Ma
Published February 1, 2019; First published January 22, 2019
Citation Information: J Clin Invest. 2019;129(2):820-833. https://doi.org/10.1172/JCI122954.
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Categories: Research Article Neuroscience

Genetic reduction of eEF2 kinase alleviates pathophysiology in Alzheimer’s disease model mice

Abstract

Molecular signaling mechanisms underlying Alzheimer’s disease (AD) remain unclear. Maintenance of memory and synaptic plasticity depend on de novo protein synthesis, dysregulation of which is implicated in AD. Recent studies showed AD-associated hyperphosphorylation of mRNA translation factor eukaryotic elongation factor 2 (eEF2), which results in inhibition of protein synthesis. We tested to determine whether suppression of eEF2 phosphorylation could improve protein synthesis capacity and AD-associated cognitive and synaptic impairments. Genetic reduction of the eEF2 kinase (eEF2K) in 2 AD mouse models suppressed AD-associated eEF2 hyperphosphorylation and improved memory deficits and hippocampal long-term potentiation (LTP) impairments without altering brain amyloid β (Aβ) pathology. Furthermore, eEF2K reduction alleviated AD-associated defects in dendritic spine morphology, postsynaptic density formation, de novo protein synthesis, and dendritic polyribosome assembly. Our results link eEF2K/eEF2 signaling dysregulation to AD pathophysiology and therefore offer a feasible therapeutic target.

Authors

Brenna C. Beckelman, Wenzhong Yang, Nicole P. Kasica, Helena R. Zimmermann, Xueyan Zhou, C. Dirk Keene, Alexey G. Ryazanov, Tao Ma

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Figure 1

Hyperphosphorylation of eEF2 in the AD hippocampus.

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Hyperphosphorylation of eEF2 in the AD hippocampus. (A) Postmortem human...
(A) Postmortem human hippocampal lysates from AD patients exhibit increased eEF2 phosphorylation compared with those of age-matched controls (CT). n = 9. *P < 0.05, unpaired t test. (B) Human postmortem hippocampal tissue from FTD patients shows decreased eEF2 phosphorylation compared with that of healthy controls. Controls, n = 8; FTD, n = 5. **P < 0.01, unpaired t test. (C) eEF2 phosphorylation is not affected in hippocampal tissue from LBD patients (n = 4) compared with that of age-matched controls. n = 5. P = 0.99, unpaired t test. Error bars for human patient data indicate ± SEM. (D) Representative images demonstrating hyperphosphorylation of eEF2 in the AD hippocampus. Insets are shown at ×60 magnification. Scale bars: 300 μm (×20); 40 μm (×60). Immunohistochemical experiments were replicated 3 times. (E) Genetic reduction of eEF2K corrects eEF2 hyperphosphorylation in hippocampal lysates from Tg19959 AD model mice. n = 10. *P < 0.05; **P < 0.01, 1-way ANOVA with Tukey’s post hoc test. (F) Representative images from SUnSET puromycin incorporation assay. Image shows 10–250 kDa range. (G) Quantification of de novo protein synthesis via SUnSET assay. WT, n = 6 mice; Tg19959, n = 5; eEF2K+/–, n = 4; Tg19959/eEF2K+/–, n = 8. *P < 0.05; ***P < 0.001, 1-way ANOVA with Tukey’s post hoc test. Box and whisker plots represent the interquartile range, with the line across the box indicating the median. Whiskers show the highest and lowest values detected.