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 January 22, 2019
Citation Information: J Clin Invest. 2019;129(2):820-833. https://doi.org/10.1172/JCI122954.
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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 4

Genetic reduction of eEF2K restores spine density in hippocampus from Tg19959 mice.

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Genetic reduction of eEF2K restores spine density in hippocampus from Tg...
(A) Representative images from Golgi-Cox stain of area CA1 dendritic spines. Original magnification, ×100. Scale bar: 12 μm. (B) Total CA1 spine density per 100 μm. WT, n = 34 dendrites; Tg19559, n = 58; eEF2K+/–, n = 40; Tg19959/eEF2K+/–, n = 50. (C) Mature spine density per 100 μm. Branched and mushroom type spines were classified as mature. (D) Immature spine density per 100 μm. Thin and filopodial spines were classified as immature. (E) Representative TEM images for CA1 PSDs. n = 3 mice per genotype. Original magnification, ×11,000. Scale bar: 500 nm. (F) Number of PSDs per μm2. *P < 0.05; **P < 0.01; ***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.