Suppression of mRNA translational factor eEF2 phosphorylation alleviates cognitive and synaptic deficits in mouse models of Alzheimer’s disease

Identification: Ma, Tao


Description

Suppression of mRNA translational factor eEF2 phosphorylation alleviates cognitive and synaptic deficits in mouse models of Alzheimer's disease
 
Brenna C. Beckelman1, Wenzhong Yang1, Nicole P. Kasica1, Helena R. Zimmermann1, Xueyan Zhou1, C. Dirk Keene2, George A. Carlson3, Alexey G. Ryazanov4, Tao Ma1*
1Department of Internal Medicine, Gerontology & Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; 2Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA; 3McLaughlin Research Institute, Great Falls, MT, USA; 4Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA
*Corresponding author: Dr. Tao Ma, Department of Internal Medicine-Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 USA - tma@wakehealth.edu
 
The basic molecular signaling mechanisms underlying Alzheimer's disease (AD) remain unclear. Maintenance of memory and synaptic plasticity depends on de novo protein synthesis, dysregulation of which is implicated in AD. Recent studies showed AD-associated hyper-phosphorylation of mRNA translational factor eEF2, which results in inhibition of protein synthesis. We tested whether restoration of eEF2 phosphorylation and thus protein synthesis capacity could improve AD-associated cognitive and synaptic impairments.     Genetic reduction of the eEF2 kinase (eEF2K) in two AD mouse models improved AD-associated eEF2 hyper-phosphorylation,   memory deficits and hippocampal long-term potentiation (LTP) impairments, without altering brain Aβ pathology. Furthermore, eEF2K reduction alleviated AD-associated defects in dendritic spine morphology, post-synaptic density formation, de novo protein synthesis, and dendritic polyribosome development. Our results link eEF2K/eEF2 signaling dysregulation to AD pathophysiology and therefore a feasible therapeutic target.
 
Funding: This work was supported by National Institutes of Health grants K99/R00 AG044469, R01 AG055581, R01 AG056622 (T.M.), F31AG055264 (H.R.Z), and F31AG054113 (B.C.B.), the Alzheimer's Association grant NIRG-15-362799 (T.M.), the BrightFocus Foundation grant A2017457S, Wake Forest Alzheimer's Disease Core Center (ADCC) pilot grant (T.M.), Wake Forest Clinical and Translational Science Institute (CTSI) pilot grant (T.M.).
 

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