Acta Neuropathologica

, Volume 133, Issue 1, pp 101–119 | Cite as

eEF2K inhibition blocks Aβ42 neurotoxicity by promoting an NRF2 antioxidant response

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

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.

Keywords

eEF2K Alzheimer’s disease Aβ oligomers mRNA translation Oxidative stress NRF2 

Supplementary material

401_2016_1634_MOESM1_ESM.pdf (2.2 mb)
Supplementary material 1 (PDF 2243 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Asad Jan
    • 1
    • 2
  • Brandon Jansonius
    • 2
  • Alberto Delaidelli
    • 1
    • 2
  • Syam Prakash Somasekharan
    • 2
  • Forum Bhanshali
    • 3
  • Milène Vandal
    • 4
  • Gian Luca Negri
    • 2
  • Don Moerman
    • 5
  • Ian MacKenzie
    • 1
  • Frédéric Calon
    • 4
  • Michael R. Hayden
    • 3
  • Stefan Taubert
    • 3
  • Poul H. Sorensen
    • 1
    • 2
  1. 1.Department of Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverCanada
  2. 2.British Columbia Cancer Research CentreVancouverCanada
  3. 3.Department of Medical Genetics, Child and Family Research InstituteUniversity of British Columbia, Centre for Molecular Medicine and TherapeuticsVancouverCanada
  4. 4.Faculté de PharmacieUniversité LavalQuebecCanada
  5. 5.Department of ZoologyUniversity of British ColumbiaVancouverCanada

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