Genetic reduction of eEF2 kinase alleviates pathophysiology in Alzheimer’s disease model mice
Year: 2019
Type: article
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.
DOI: 10.1172/jci122954
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: Alzheimer's Association, BrightFocus Foundation, Nancy and Buster Alvord Endowment, University of Washington, National Institutes of Health, Wake Forest School of Medicine, National Institute on Aging, National Center for Advancing Translational Sciences, Wake Forest Clinical and Translational Science Institute, Wake Forest School of Medicine
Awards: AMPK in Alzheimer's Disease-Associated Synaptic Failure and Memory Deficits, G1575942645, G171052541, Wake Forest Alzheimer's Disease Core Center, G1894923239, Role of eEF2 kinase in AD-associated synaptic failure and memory deficits, G2402332820, G2403031388, G2831378491, Alzheimer's Disease Patient Registry (ADPR/ACT), Elucidating the roles of AMPK isoforms in Alzheimer's Disease Pathogenesis, G3930819373, G5028008713, G5144998230, G5152833415, Isoform-specific roles of AMPK in synaptic failure and memory deficit in Alzheimer's Disease, G5453718779, Role of eEF2 Hyper-phosphorylation in Alzheimer's-associated Synaptic Failure and Memory Deficits, G5788851611, Role of protein synthesis in Alzheimers disease-associated impairments of synaptic plasticity and memory, G738160294, Alzheimer's Disease Research Center, G7938922167, G8165767282, G8660995804, G9000038858, G9000126387, G9000210821, G94668252
OpenAlex ID: W2911277088