Journal Article

eEF2K inhibition blocks Abeta42 neurotoxicity by promoting an NRF2 antioxidant response

Somasekharan, Syam Prakash, Bhanshali, Forum, Hayden, Michael R, Sorensen, Poul H, Delaidelli, Alberto, Calon, Frederic, Vandal, Milène, Jansonius, Brandon, MacKenzie, Ian, Moerman, Don, Taubert, Stefan, Negri, Gian Luca, Jan, Asad

2017

Overview

Soluble oligomers of amyloid-[beta] (A[beta]) 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 A[beta] 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 A[beta] oligomers activate neuronal eEF2K, suggesting a potential link to A[beta] 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 A[beta]42 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 A[beta]42 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 A[beta]42 in neurons. Taken together, these findings highlight the potential utility of eEF2K inhibition to reduce A[beta]-mediated oxidative stress in AD.

• Publisher: Springer,Springer Nature B.V
• Subject: Advertising executives / Alzheimer's disease / Amyloidosis / Antioxidants / Antioxidants (Nutrients) / Brain / Energy / Genetic engineering / Health aspects / Homeostasis / Kinases / Medical research / Memory / Metabolism / Mutation / Neurons / Neuropathology / Neurotoxicity / Oligomers / Oxidative stress / Pathogenesis / Pathology / Phosphorylation / Protein synthesis / Proteins / RNA / Translation (Genetics)