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Homozygous knockout of eEF2K alleviates cognitive deficits in APP/PS1 Alzheimer’s disease model mice independent of brain amyloid β pathology

Maintenance of memory and synaptic plasticity depends on de novo protein synthesis, and accumulating evidence implicates a role of dysregulated mRNA translation in cognitive impairments associated with Alzheimer’s disease (AD). Accumulating evidence demonstrates hyper-phosphorylation of translation...

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Autores principales: Kasica, Nicole P., Zhou, Xueyan, Jester, Hannah M., Holland, Caroline E., Ryazanov, Alexey G., Forshaw, Tom E., Furdui, Cristina M., Ma, Tao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9500344/
https://www.ncbi.nlm.nih.gov/pubmed/36158543
http://dx.doi.org/10.3389/fnagi.2022.959326
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author Kasica, Nicole P.
Zhou, Xueyan
Jester, Hannah M.
Holland, Caroline E.
Ryazanov, Alexey G.
Forshaw, Tom E.
Furdui, Cristina M.
Ma, Tao
author_facet Kasica, Nicole P.
Zhou, Xueyan
Jester, Hannah M.
Holland, Caroline E.
Ryazanov, Alexey G.
Forshaw, Tom E.
Furdui, Cristina M.
Ma, Tao
author_sort Kasica, Nicole P.
collection PubMed
description Maintenance of memory and synaptic plasticity depends on de novo protein synthesis, and accumulating evidence implicates a role of dysregulated mRNA translation in cognitive impairments associated with Alzheimer’s disease (AD). Accumulating evidence demonstrates hyper-phosphorylation of translation factor eukaryotic elongation factor 2 (eEF2) in the hippocampi of human AD patients as well as transgenic AD model mice. Phosphorylation of eEF2 (at the Thr 56 site) by its only known kinase, eEF2K, leads to inhibition of general protein synthesis. A recent study suggests that amyloid β (Aβ)-induced neurotoxicity could be associated with an interaction between eEF2 phosphorylation and the transcription factor nuclear erythroid 2-related factor (NRF2)-mediated antioxidant response. In this brief communication, we report that global homozygous knockout of the eEF2K gene alleviates deficits of long-term recognition and spatial learning in a mouse model of AD (APP/PS1). Moreover, eEF2K knockout does not alter brain Aβ pathology in APP/PS1 mice. The hippocampal NRF2 antioxidant response in the APP/PS1 mice, measured by expression levels of nicotinamide adenine dinucleotide plus hydrogen (NADPH) quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1), is ameliorated by suppression of eEF2K signaling. Together, the findings may contribute to our understanding of the molecular mechanisms underlying AD pathogenesis, indicating that suppression of eEF2K activity could be a beneficial therapeutic option for this devastating neurodegenerative disease.
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spelling pubmed-95003442022-09-24 Homozygous knockout of eEF2K alleviates cognitive deficits in APP/PS1 Alzheimer’s disease model mice independent of brain amyloid β pathology Kasica, Nicole P. Zhou, Xueyan Jester, Hannah M. Holland, Caroline E. Ryazanov, Alexey G. Forshaw, Tom E. Furdui, Cristina M. Ma, Tao Front Aging Neurosci Neuroscience Maintenance of memory and synaptic plasticity depends on de novo protein synthesis, and accumulating evidence implicates a role of dysregulated mRNA translation in cognitive impairments associated with Alzheimer’s disease (AD). Accumulating evidence demonstrates hyper-phosphorylation of translation factor eukaryotic elongation factor 2 (eEF2) in the hippocampi of human AD patients as well as transgenic AD model mice. Phosphorylation of eEF2 (at the Thr 56 site) by its only known kinase, eEF2K, leads to inhibition of general protein synthesis. A recent study suggests that amyloid β (Aβ)-induced neurotoxicity could be associated with an interaction between eEF2 phosphorylation and the transcription factor nuclear erythroid 2-related factor (NRF2)-mediated antioxidant response. In this brief communication, we report that global homozygous knockout of the eEF2K gene alleviates deficits of long-term recognition and spatial learning in a mouse model of AD (APP/PS1). Moreover, eEF2K knockout does not alter brain Aβ pathology in APP/PS1 mice. The hippocampal NRF2 antioxidant response in the APP/PS1 mice, measured by expression levels of nicotinamide adenine dinucleotide plus hydrogen (NADPH) quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1), is ameliorated by suppression of eEF2K signaling. Together, the findings may contribute to our understanding of the molecular mechanisms underlying AD pathogenesis, indicating that suppression of eEF2K activity could be a beneficial therapeutic option for this devastating neurodegenerative disease. Frontiers Media S.A. 2022-09-09 /pmc/articles/PMC9500344/ /pubmed/36158543 http://dx.doi.org/10.3389/fnagi.2022.959326 Text en Copyright © 2022 Kasica, Zhou, Jester, Holland, Ryazanov, Forshaw, Furdui and Ma. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Kasica, Nicole P.
Zhou, Xueyan
Jester, Hannah M.
Holland, Caroline E.
Ryazanov, Alexey G.
Forshaw, Tom E.
Furdui, Cristina M.
Ma, Tao
Homozygous knockout of eEF2K alleviates cognitive deficits in APP/PS1 Alzheimer’s disease model mice independent of brain amyloid β pathology
title Homozygous knockout of eEF2K alleviates cognitive deficits in APP/PS1 Alzheimer’s disease model mice independent of brain amyloid β pathology
title_full Homozygous knockout of eEF2K alleviates cognitive deficits in APP/PS1 Alzheimer’s disease model mice independent of brain amyloid β pathology
title_fullStr Homozygous knockout of eEF2K alleviates cognitive deficits in APP/PS1 Alzheimer’s disease model mice independent of brain amyloid β pathology
title_full_unstemmed Homozygous knockout of eEF2K alleviates cognitive deficits in APP/PS1 Alzheimer’s disease model mice independent of brain amyloid β pathology
title_short Homozygous knockout of eEF2K alleviates cognitive deficits in APP/PS1 Alzheimer’s disease model mice independent of brain amyloid β pathology
title_sort homozygous knockout of eef2k alleviates cognitive deficits in app/ps1 alzheimer’s disease model mice independent of brain amyloid β pathology
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9500344/
https://www.ncbi.nlm.nih.gov/pubmed/36158543
http://dx.doi.org/10.3389/fnagi.2022.959326
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