Skip to main content

Advertisement

SpringerLink
Log in

eEF2K inhibition blocks Aβ42 neurotoxicity by promoting an NRF2 antioxidant response

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Alonso-Nanclares L, Merino-Serrais P, Gonzalez S, DeFelipe J (2013) Synaptic changes in the dentate gyrus of APP/PS1 transgenic mice revealed by electron microscopy. J Neuropathol Exp Neurol 72:386–395. doi:10.1097/NEN.0b013e31828d41ec

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Baxter PS, Bell KF, Hasel P, Kaindl AM, Fricker M, Thomson D et al (2015) Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system. Nat Commun 6:6761. doi:10.1038/ncomms7761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bender CL, Yang Q, Sun L, Liu SJ (2016) NH125 reduces the level of CPEB3, an RNA binding protein, to promote synaptic GluA2 expression. Neuropharmacology 101:531–537. doi:10.1016/j.neuropharm.2015.03.017

    Article  CAS  PubMed  Google Scholar 

  4. Boyce M, Py BF, Ryazanov AG, Minden JS, Long K, Ma D et al (2008) A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death. Cell Death Differ 15:589–599. doi:10.1038/sj.cdd.4402296

    Article  CAS  PubMed  Google Scholar 

  5. Brenner S (1974) The genetics of Caenorhabditis elegans. Genetics 77:71–94

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Bryan HK, Olayanju A, Goldring CE, Park BK (2013) The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. Biochem Pharmacol 85:705–717. doi:10.1016/j.bcp.2012.11.016

    Article  CAS  PubMed  Google Scholar 

  7. Busche MA, Chen X, Henning HA, Reichwald J, Staufenbiel M, Sakmann B et al (2012) Critical role of soluble amyloid-beta for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 109:8740–8745. doi:10.1073/pnas.1206171109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Carrera I, Etcheverria I, Li Y, Fernandez-Novoa L, Lombardi V, Vigo C et al (2013) Immunocytochemical characterization of Alzheimer disease hallmarks in APP/PS1 transgenic mice treated with a new anti-amyloid-beta vaccine. Biomed Res Int 2013:709145. doi:10.1155/2013/709145

    Article  PubMed  PubMed Central  Google Scholar 

  9. Chen Z, Gopalakrishnan SM, Bui MH, Soni NB, Warrior U, Johnson EF et al (2011) 1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125) induces phosphorylation of eukaryotic elongation factor-2 (eEF2): a cautionary note on the anticancer mechanism of an eEF2 kinase inhibitor. J Biol Chem 286:43951–43958. doi:10.1074/jbc.M111.301291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chu HP, Liao Y, Novak JS, Hu Z, Merkin JJ, Shymkiv Y et al (2014) Germline quality control: eEF2K stands guard to eliminate defective oocytes. Dev Cell 28:561–572. doi:10.1016/j.devcel.2014.01.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chuang TT (2010) Neurogenesis in mouse models of Alzheimer’s disease. Biochim Biophys Acta 1802:872–880. doi:10.1016/j.bbadis.2009.12.008

    Article  CAS  PubMed  Google Scholar 

  12. De Strooper B, Karran E (2016) The cellular phase of Alzheimer’s disease. Cell 164:603–615. doi:10.1016/j.cell.2015.12.056

    Article  PubMed  Google Scholar 

  13. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112. doi:10.1038/nrm2101

    Article  CAS  PubMed  Google Scholar 

  14. Habas A, Hahn J, Wang X, Margeta M (2013) Neuronal activity regulates astrocytic Nrf2 signaling. Proc Natl Acad Sci USA 110:18291–18296. doi:10.1073/pnas.1208764110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hamilton A, Vasefi M, Vander Tuin C, McQuaid RJ, Anisman H, Ferguson SS (2016) Chronic pharmacological mGluR5 inhibition prevents cognitive impairment and reduces pathogenesis in an alzheimer disease mouse model. Cell Rep 15:1859–1865. doi:10.1016/j.celrep.2016.04.077

    Article  CAS  PubMed  Google Scholar 

  16. Harada A, Teng J, Takei Y, Oguchi K, Hirokawa N (2002) MAP2 is required for dendrite elongation, PKA anchoring in dendrites, and proper PKA signal transduction. J Cell Biol 158:541–549. doi:10.1083/jcb.200110134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Harder B, Jiang T, Wu T, Tao S, de la Vega MR, Tian W et al (2015) Molecular mechanisms of Nrf2 regulation and how these influence chemical modulation for disease intervention. Biochem Soc Trans 43:680–686. doi:10.1042/BST20150020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Heise C, Gardoni F, Culotta L, di Luca M, Verpelli C, Sala C (2014) Elongation factor-2 phosphorylation in dendrites and the regulation of dendritic mRNA translation in neurons. Front Cell Neurosci 8:35. doi:10.3389/fncel.2014.00035

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hobert O (2003) Behavioral plasticity in C. elegans: paradigms, circuits, genes. J Neurobiol 54:203–223. doi:10.1002/neu.10168

    Article  CAS  PubMed  Google Scholar 

  20. Jan A, Adolfsson O, Allaman I, Buccarello AL, Magistretti PJ, Pfeifer A et al (2010) A{beta}42 neurotoxicity is mediated by ongoing nucleated polymerization process rather than by discrete A{beta}42 species. J Biol Chem. doi:10.1074/jbc.M110.172411

    PubMed  PubMed Central  Google Scholar 

  21. Jan A, Hartley DM, Lashuel HA (2010) Preparation and characterization of toxic A[beta] aggregates for structural and functional studies in Alzheimer’s disease research. Nat Protocols 5:1186–1209. http://www.nature.com/nprot/journal/v5/n6/suppinfo/nprot.2010.72_S1.html

  22. Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA et al (2004) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13:159–170

    Article  CAS  PubMed  Google Scholar 

  23. Johnson DA, Johnson JA (2015) Nrf2–a therapeutic target for the treatment of neurodegenerative diseases. Free Radic Biol Med 88:253–267. doi:10.1016/j.freeradbiomed.2015.07.147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Keith D, El-Husseini A (2008) Excitation control: balancing PSD-95 function at the synapse. Front Mol Neurosci 1:4. doi:10.3389/neuro.02.004.2008

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kenney JW, Moore CE, Wang X, Proud CG (2014) Eukaryotic elongation factor 2 kinase, an unusual enzyme with multiple roles. Adv Biol Regul 55:15–27. doi:10.1016/j.jbior.2014.04.003

    Article  CAS  PubMed  Google Scholar 

  26. Kessels HW, Nabavi S, Malinow R (2013) Metabotropic NMDA receptor function is required for beta-amyloid-induced synaptic depression. Proc Natl Acad Sci USA 110:4033–4038. doi:10.1073/pnas.1219605110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M et al (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95:6448–6453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lansbury PT, Lashuel HA (2006) A century-old debate on protein aggregation and neurodegeneration enters the clinic. Nature 443:774–779. doi:10.1038/nature05290

    Article  CAS  PubMed  Google Scholar 

  29. Leprivier G, Remke M, Rotblat B, Dubuc A, Mateo AR, Kool M et al (2013) The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation. Cell 153:1064–1079. doi:10.1016/j.cell.2013.04.055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. LeVine H 3rd, Walker LC (2016) What amyloid ligands can tell us about molecular polymorphism and disease. Neurobiol Aging 42:205–212. doi:10.1016/j.neurobiolaging.2016.03.019

    Article  CAS  PubMed  Google Scholar 

  31. Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D (2009) Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62:788–801. doi:10.1016/j.neuron.2009.05.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li X, Alafuzoff I, Soininen H, Winblad B, Pei JJ (2005) Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer’s disease brain. FEBS J 272:4211–4220. doi:10.1111/j.1742-4658.2005.04833.x

    Article  CAS  PubMed  Google Scholar 

  33. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795. doi:10.1038/nature05292

    Article  CAS  PubMed  Google Scholar 

  34. Liu R, Proud CG (2016) Eukaryotic elongation factor 2 kinase as a drug target in cancer, and in cardiovascular and neurodegenerative diseases. Acta Pharmacol Sin 37:285–294. doi:10.1038/aps.2015.123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lu T, Aron L, Zullo J, Pan Y, Kim H, Chen Y et al (2014) REST and stress resistance in ageing and Alzheimer’s disease. Nature 507:448–454. doi:10.1038/nature13163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ma T, Chen Y, Vingtdeux V, Zhao H, Viollet B, Marambaud P et al (2014) Inhibition of AMP-activated protein kinase signaling alleviates impairments in hippocampal synaptic plasticity induced by amyloid beta. J Neurosci 34:12230–12238. doi:10.1523/JNEUROSCI.1694-14.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Manzoni C, Colombo L, Bigini P, Diana V, Cagnotto A, Messa M et al (2011) The molecular assembly of amyloid abeta controls its neurotoxicity and binding to cellular proteins. PLoS One 6:e24909. doi:10.1371/journal.pone.0024909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Margie O, Palmer C, Chin-Sang I (2013) C. elegans chemotaxis assay. J Vis Exp e50069. doi:10.3791/50069

  39. Ming GL, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70:687–702. doi:10.1016/j.neuron.2011.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mitsuishi Y, Motohashi H, Yamamoto M (2012) The Keap1-Nrf2 system in cancers: stress response and anabolic metabolism. Front Oncol 2:200. doi:10.3389/fonc.2012.00200

    Article  PubMed  PubMed Central  Google Scholar 

  41. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R et al. (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421. doi:S0896627303004343 [pii]

  42. Ramsey CP, Glass CA, Montgomery MB, Lindl KA, Ritson GP, Chia LA et al (2007) Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol 66:75–85. doi:10.1097/nen.0b013e31802d6da9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Roselli F, Tirard M, Lu J, Hutzler P, Lamberti P, Livrea P et al (2005) Soluble beta-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. JNeurosci 25:11061–11070

    Article  CAS  Google Scholar 

  44. Rotblat B, Southwell AL, Ehrnhoefer DE, Skotte NH, Metzler M, Franciosi S et al (2014) HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response. Proc Natl Acad Sci USA 111:3032–3037. doi:10.1073/pnas.1314421111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ryazanov AG (2002) Elongation factor-2 kinase and its newly discovered relatives. FEBS Lett 514:26–29. doi:10.1016/S0014-5793(02)02299-8

    Article  CAS  PubMed  Google Scholar 

  46. Sakamoto S, Ishii K, Sasaki M, Hosaka K, Mori T, Matsui M et al (2002) Differences in cerebral metabolic impairment between early and late onset types of Alzheimer’s disease. J Neurol Sci 200:27–32. doi:10.1016/S0022-510X(02)00114-4

    Article  CAS  PubMed  Google Scholar 

  47. Salminen A, Kaarniranta K, Haapasalo A, Soininen H, Hiltunen M (2011) AMP-activated protein kinase: a potential player in Alzheimer’s disease. J Neurochem 118:460–474. doi:10.1111/j.1471-4159.2011.07331.x

    Article  CAS  PubMed  Google Scholar 

  48. Saraiva LM, Seixas da Silva GS, Galina A, da-Silva WS, da-Silva WS, Klein WL, Ferreira ST et al (2010) Amyloid-beta triggers the release of neuronal hexokinase 1 from mitochondria. PLoS One 5:e15230. doi:10.1371/journal.pone.0015230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Savonenko A, Xu GM, Melnikova T, Morton JL, Gonzales V, Wong MP et al (2005) Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer’s disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities. Neurobiol Dis 18:602–617. doi:10.1016/j.nbd.2004.10.022

    Article  CAS  PubMed  Google Scholar 

  50. Sawin ER, Ranganathan R, Horvitz HR (2000) C. elegans locomotory rate is modulated by the environment through a dopaminergic pathway and by experience through a serotonergic pathway. Neuron 26:619–631. doi:10.1016/S0896-6273(00)81199-X

    Article  CAS  PubMed  Google Scholar 

  51. Scheetz AJ, Nairn AC, Constantine-Paton M (2000) NMDA receptor-mediated control of protein synthesis at developing synapses. Nat Neurosci 3:211–216. doi:10.1038/72915

    Article  CAS  PubMed  Google Scholar 

  52. Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766

    CAS  PubMed  Google Scholar 

  53. Selkoe DJ (2008) Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 192:106–113. doi:10.1016/j.bbr.2008.02.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Selkoe DJ (2013) The therapeutics of Alzheimer’s disease: where we stand and where we are heading. Ann Neurol 74:328–336. doi:10.1002/ana.24001

    Article  CAS  PubMed  Google Scholar 

  55. Selkoe DJ, Schenk D (2003) Alzheimer’s disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol 43:545–584

    Article  CAS  PubMed  Google Scholar 

  56. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011) Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1:a006189. doi:10.1101/cshperspect.a006189

    Article  PubMed  PubMed Central  Google Scholar 

  57. Sutton MA, Taylor AM, Ito HT, Pham A, Schuman EM (2007) Postsynaptic decoding of neural activity: eEF2 as a biochemical sensor coupling miniature synaptic transmission to local protein synthesis. Neuron 55:648–661. doi:10.1016/j.neuron.2007.07.030

    Article  CAS  PubMed  Google Scholar 

  58. Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800

    Article  PubMed  Google Scholar 

  59. Tremblay RG, Sikorska M, Sandhu JK, Lanthier P, Ribecco-Lutkiewicz M, Bani-Yaghoub M (2010) Differentiation of mouse Neuro 2A cells into dopamine neurons. J Neurosci Methods 186:60–67. doi:10.1016/j.jneumeth.2009.11.004

    Article  CAS  PubMed  Google Scholar 

  60. Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M, Takahashi H et al (2013) Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer abeta oligomer bound to cellular prion protein. Neuron 79:887–902. doi:10.1016/j.neuron.2013.06.036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Vandal M, White PJ, Tournissac M, Tremblay C, St-Amour I, Drouin-Ouellet J et al (2016) Impaired thermoregulation and beneficial effects of thermoneutrality in the 3xTg-AD model of Alzheimer’s disease. Neurobiol Aging 43:47–57. doi:10.1016/j.neurobiolaging.2016.03.024

    Article  CAS  PubMed  Google Scholar 

  62. Vargas MR, Johnson DA, Sirkis DW, Messing A, Johnson JA (2008) Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J Neurosci 28:13574–13581. doi:10.1523/JNEUROSCI.4099-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Walsh DM, Hartley DM, Kusumoto Y, Fezoui Y, Condron MM, Lomakin A et al (1999) Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates. JBiolChem 274:25945–25952

    CAS  Google Scholar 

  64. Wang HW, Pasternak JF, Kuo H, Ristic H, Lambert MP, Chromy B et al (2002) Soluble oligomers of beta amyloid (1–42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res 924:133–140. doi:10.1016/S0006-8993(01)03058-X

    Article  CAS  PubMed  Google Scholar 

  65. Wilcock DM, Gordon MN, Morgan D (2006) Quantification of cerebral amyloid angiopathy and parenchymal amyloid plaques with Congo red histochemical stain. Nat Protoc 1:1591–1595. doi:10.1038/nprot.2006.277

    Article  CAS  PubMed  Google Scholar 

  66. Wisniewski T, Goni F (2015) Immunotherapeutic approaches for Alzheimer’s disease. Neuron 85:1162–1176. doi:10.1016/j.neuron.2014.12.064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wu Y, Wu Z, Butko P, Christen Y, Lambert MP, Klein WL et al (2006) Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J Neurosci 26:13102–13113. doi:10.1523/JNEUROSCI.3448-06.2006

    Article  CAS  PubMed  Google Scholar 

  68. Xie H, Hou S, Jiang J, Sekutowicz M, Kelly J, Bacskai BJ (2013) Rapid cell death is preceded by amyloid plaque-mediated oxidative stress. Proc Natl Acad Sci USA 110:7904–7909. doi:10.1073/pnas.1217938110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the Ride2Survive Brain Cancer Impact Grant of the Canadian Cancer Society and Brain Canada (grant #703205), and funds from the BC Cancer Foundation, to PHS, a postdoctoral fellowship from the Canadian Institutes of Health Research to AJ, and a Tier 2 Canadian Research Chair in Transcriptional Regulatory Networks to ST. The authors would like to thank Amy Li, Haifeng Zhang, Jordan Cran, Arash Samiei, and David Ko for their assistance.

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada

    Asad Jan, Alberto Delaidelli, Ian MacKenzie & Poul H. Sorensen

  2. British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada

    Asad Jan, Brandon Jansonius, Alberto Delaidelli, Syam Prakash Somasekharan, Gian Luca Negri & Poul H. Sorensen

  3. Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Centre for Molecular Medicine and Therapeutics, Vancouver, BC, V5Z 4H4, Canada

    Forum Bhanshali, Michael R. Hayden & Stefan Taubert

  4. Faculté de Pharmacie, Université Laval, Pavillon Ferdinand-Vandry 1050, Avenue de la Médecine, Quebec, QC, G1V 0A6, Canada

    Milène Vandal & Frédéric Calon

  5. Department of Zoology, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada

    Don Moerman

Authors
  1. Asad Jan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brandon Jansonius
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alberto Delaidelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Syam Prakash Somasekharan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Forum Bhanshali
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Milène Vandal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gian Luca Negri
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Don Moerman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ian MacKenzie
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Frédéric Calon
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michael R. Hayden
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Stefan Taubert
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Poul H. Sorensen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Poul H. Sorensen.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 2243 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jan, A., Jansonius, B., Delaidelli, A. et al. eEF2K inhibition blocks Aβ42 neurotoxicity by promoting an NRF2 antioxidant response. Acta Neuropathol 133, 101–119 (2017). https://doi.org/10.1007/s00401-016-1634-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-016-1634-1

Keywords

Search

Navigation