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 3

Amyloid plaque deposition in Tg19959 AD model mice is not affected by genetic reduction of eEF2K.

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Amyloid plaque deposition in Tg19959 AD model mice is not affected by ge...
(A) Representative images of hippocampal plaque deposition in WT, Tg19959, eEF2K+/–, and Tg19959/eEF2K+/– mice. Insets are shown at ×60 magnification. Scale bars: 300 μm (×20); 40 μm (×60). (B) Percentage of hippocampal area covered in amyloid plaques in Tg19959 (n = 9 sections) and Tg19959/eEF2K+/– mice (n = 10). P = 0.68, unpaired t test. (C) Representative images of somatosensory cortical plaque deposition in WT, Tg19959, eEF2K+/–, and Tg19959/eEF2K+/– mice. Insets are shown at ×60 magnification. Scale bars: 300 μm (×20); 40 μm (×60). (D) Percentage of cortical area covered by amyloid plaques in Tg19959 and Tg19959/eEF2K+/– mice. P = 0.33, unpaired t 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. (E) ELISA showed no differences in levels of Aβ 1–42 or Aβ 1–40 oligomers (F) in Tg19959 and Tg19959/eEF2K+/– forebrain tissue. n = 8. P = 0.32 for Aβ 1-42; P = 0.11 for Aβ 1-40, unpaired t test. ELISAs were performed in triplicate. Error bars represent ± SEM.