title: eEF2K inhibition blocks Aβ42 neurotoxicity by promoting an NRF2 antioxidant response.
abstract: Soluble oligomers of amyloid-β (Aβ) impair synaptic plasticity, perturb neuronal energy homeostasis, and are implicated in Alzheimer's disease (AD) pathogenesis. Therefore, significant efforts in AD drug discovery research aim to prevent the formation of Aβ oligomers or block their neurotoxicity. The eukaryotic elongation factor-2 kinase (eEF2K) plays a critical role in synaptic plasticity, and couples neurotransmission to local dendritic mRNA translation. Recent evidence indicates that Aβ oligomers activate neuronal eEF2K, suggesting a potential link to Aβ induced synaptic dysfunction. However, a detailed understanding of the role of eEF2K in AD pathogenesis, and therapeutic potential of eEF2K inhibition in AD, remain to be determined. Here, we show that eEF2K activity is increased in postmortem AD patient cortex and hippocampus, and in the hippocampus of aged transgenic AD mice. Furthermore, eEF2K inhibition using pharmacological or genetic approaches prevented the toxic effects of Aβ42 oligomers on neuronal viability and dendrite formation in vitro. We also report that eEF2K inhibition promotes the nuclear factor erythroid 2-related factor (NRF2) antioxidant response in neuronal cells, which was crucial for the beneficial effects of eEF2K inhibition in neurons exposed to Aβ42 oligomers. Accordingly, NRF2 knockdown or overexpression of the NRF2 inhibitor, Kelch-Like ECH-Associated Protein-1 (Keap1), significantly attenuated the neuroprotection associated with eEF2K inhibition. Finally, genetic deletion of the eEF2K ortholog efk-1 reduced oxidative stress, and improved chemotaxis and serotonin sensitivity in C. elegans expressing human Aβ42 in neurons. Taken together, these findings highlight the potential utility of eEF2K inhibition to reduce Aβ-mediated oxidative stress in AD.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.|British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Asad
authors.initials: A
authors.lastname: Jan
authors.affiliation: British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Brandon
authors.initials: B
authors.lastname: Jansonius
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.|British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Alberto
authors.initials: A
authors.lastname: Delaidelli
authors.affiliation: British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Syam Prakash
authors.initials: SP
authors.lastname: Somasekharan
authors.affiliation: Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Centre for Molecular Medicine and Therapeutics, Vancouver, BC, V5Z 4H4, Canada.
authors.forename: Forum
authors.initials: F
authors.lastname: Bhanshali
authors.affiliation: Faculté de Pharmacie, Université Laval, Pavillon Ferdinand-Vandry 1050, Avenue de la Médecine, Quebec, QC, G1V 0A6, Canada.
authors.forename: Milène
authors.initials: M
authors.lastname: Vandal
authors.affiliation: British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Gian Luca
authors.initials: GL
authors.lastname: Negri
authors.affiliation: Department of Zoology, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: Don
authors.initials: D
authors.lastname: Moerman
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: MacKenzie
authors.affiliation: Faculté de Pharmacie, Université Laval, Pavillon Ferdinand-Vandry 1050, Avenue de la Médecine, Quebec, QC, G1V 0A6, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Calon
authors.affiliation: Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Centre for Molecular Medicine and Therapeutics, Vancouver, BC, V5Z 4H4, Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Centre for Molecular Medicine and Therapeutics, Vancouver, BC, V5Z 4H4, Canada.
authors.forename: Stefan
authors.initials: S
authors.lastname: Taubert
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada. psor@mail.ubc.ca.|British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. psor@mail.ubc.ca.
authors.forename: Poul H
authors.initials: PH
authors.lastname: Sorensen
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D054736:Elongation Factor 2 Kinase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000201:enzymology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D017382:Reactive Oxygen Species
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); C517689:EEF2K protein, human; C517690:Eef2k protein, mouse; D054736:Elongation Factor 2 Kinase
keywords: Alzheimer’s disease; Aβ oligomers; NRF2; Oxidative stress; eEF2K; mRNA translation