eEF2K inhibition blocks Aβ42 neurotoxicity by promoting an NRF2 antioxidant response

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• 作者：Asad Jan ; Brandon Jansonius ; Alberto Delaidelli…
• 关键词：eEF2K ; Alzheimer’s disease ; Aβ oligomers ; mRNA translation ; Oxidative stress ; NRF2
• 刊名：Acta Neuropathologica
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：133
• 期：1
• 页码：101-119
• 全文大小：
• 刊物类别：Medicine
• 刊物主题：Pathology; Neurosciences;
• 出版者：Springer Berlin Heidelberg
• ISSN：1432-0533
• 卷排序：133

文摘

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.