Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Suppression of eIF2α kinases alleviates Alzheimer's disease–related plasticity and memory deficits

Abstract

Expression of long-lasting synaptic plasticity and long-term memory requires protein synthesis, which can be repressed by phosphorylation of eukaryotic initiation factor 2 α-subunit (eIF2α). Elevated phosphorylation of eIF2α has been observed in the brains of Alzheimer's disease patients and Alzheimer's disease model mice. Therefore, we tested whether suppressing eIF2α kinases could alleviate synaptic plasticity and memory deficits in Alzheimer's disease model mice. Genetic deletion of eIF2α kinase PERK prevented enhanced phosphorylation of eIF2α and deficits in protein synthesis, synaptic plasticity and spatial memory in mice that express familial Alzheimer's disease–related mutations in APP and PSEN1. Similarly, deletion of another eIF2α kinase, GCN2, prevented impairments of synaptic plasticity and defects in spatial memory exhibited by the Alzheimer's disease model mice. Our findings implicate aberrant eIF2α phosphorylation as a previously unidentified molecular mechanism underlying Alzheimer's disease–related synaptic pathophysioloy and memory dysfunction and suggest that PERK and GCN2 are potential therapeutic targets for treatment of individuals with Alzheimer's disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Increased eIF2α phosphorylation in Alzheimer's disease.
Figure 2: Aβ-induced impairment in LTP is alleviated by deleting the eIF2α kinase PERK.
Figure 3: Generation of Alzheimer's disease model mice with diminished PERK-eIF2α signaling.
Figure 4: Spatial memory deficits in APP-PS1 Alzheimer's disease model mice are alleviated by suppressing PERK-eIF2α signaling.
Figure 5: LTP impairments in APP-PS1 mice are rescued by decreasing PERK-eIF2α signaling.
Figure 6: Removal of GCN2 reverses Alzheimer's disease-associated LTP failure.
Figure 7: Spatial memory deficits in APP-PS1 Alzheimer's disease model mice are alleviated by deleting the eIF2α kinase GCN2.

Similar content being viewed by others

References

  1. Holtzman, D.M., Morris, J.C. & Goate, A.M. Alzheimer's disease: the challenge of the second century. Sci. Transl. Med. 3, sr71 (2011).

    Google Scholar 

  2. Querfurth, H.W. & LaFerla, F.M. Alzheimer's disease. N. Engl. J. Med. 362, 329–344 (2010).

    Article  CAS  Google Scholar 

  3. Selkoe, D.J. Resolving controversies on the path to Alzheimer's therapeutics. Nat. Med. 17, 1060–1065 (2011).

    Article  CAS  Google Scholar 

  4. Haass, C. & Selkoe, D.J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat. Rev. Mol. Cell Biol. 8, 101–112 (2007).

    Article  CAS  Google Scholar 

  5. Costa-Mattioli, M., Sossin, W.S., Klann, E. & Sonenberg, N. Translational control of long-lasting synaptic plasticity and memory. Neuron 61, 10–26 (2009).

    Article  CAS  Google Scholar 

  6. Klann, E. & Dever, T.E. Biochemical mechanisms for translational regulation in synaptic plasticity. Nat. Rev. Neurosci. 5, 931–942 (2004).

    Article  CAS  Google Scholar 

  7. Costa-Mattioli, M. et al. Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. Nature 436, 1166–1173 (2005).

    Article  CAS  Google Scholar 

  8. Costa-Mattioli, M. et al. eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell 129, 195–206 (2007).

    Article  CAS  Google Scholar 

  9. Jiang, Z. et al. eIF2alpha Phosphorylation-dependent translation in CA1 pyramidal cells impairs hippocampal memory consolidation without affecting general translation. J. Neurosci. 30, 2582–2594 (2010).

    Article  CAS  Google Scholar 

  10. Klann, E., Antion, M.D., Banko, J.L. & Hou, L. Synaptic plasticity and translation initiation. Learn. Mem. 11, 365–372 (2004).

    Article  Google Scholar 

  11. Wek, R.C., Jiang, H.-Y. & Anthony, T.G. Coping with stress: eIF2 kinases and translational control. Biochem. Soc. Trans. 34, 7–11 (2006).

    Article  CAS  Google Scholar 

  12. Chang, R., Wong, A., Ng, H. & Hugon, J. Phosphorylation of eukaryotic initiation factor-2alpha (eIF2alpha) is associated with neuronal degeneration in Alzheimer's disease. Neuroreport 13, 2429–2432 (2002).

    Article  CAS  Google Scholar 

  13. Kim, S.M. et al. Activation of eukaryotic initiation factor-2 α-kinases in okadaic acid-treated neurons. Neuroscience 169, 1831–1839 (2010).

    Article  CAS  Google Scholar 

  14. O'Connor, T. et al. Phosphorylation of the translation initiation factor eIF2α increases BACE1 levels and promotes amyloidogenesis. Neuron 60, 988–1009 (2008).

    Article  CAS  Google Scholar 

  15. Jankowsky, J.L. et al. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol. Eng. 17, 157–165 (2001).

    Article  CAS  Google Scholar 

  16. Zhang, P. et al. The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol. Cell Biol. 22, 3864–3874 (2002).

    Article  CAS  Google Scholar 

  17. Hoeffer, C.A. et al. Removal of FKBP12 enhances mTOR-Raptor interactions, LTP, memory, and perseverative/repetitive behavior. Neuron 60, 832–845 (2008).

    Article  CAS  Google Scholar 

  18. Trinh, M.A. et al. Brain-specific disruption of the eIF2α kinase PERK decreases ATF4 expression and impairs behavioral flexibility. Cell Rep. 1, 676–688 (2012).

    Article  CAS  Google Scholar 

  19. Schmidt, E.K., Clavarino, G., Ceppi, M. & Pierre, P. SUnSET, a nonradioactive method to monitor protein synthesis. Nat. Methods 6, 275–277 (2009).

    Article  CAS  Google Scholar 

  20. Cohen, E. et al. Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell 139, 1157–1169 (2009).

    Article  CAS  Google Scholar 

  21. Ma, T. et al. Amyloid β-induced impairments in hippocampal synaptic plasticity are rescued by decreasing mitochondrial superoxide. J. Neurosci. 31, 5589–5595 (2011).

    Article  CAS  Google Scholar 

  22. Palam, L.R., Baird, T.D. & Wek, R.C. Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation. J. Biol. Chem. 286, 10939–10949 (2011).

    Article  CAS  Google Scholar 

  23. Li, G., Scull, C., Ozcan, L. & Tabas, I. NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis. J. Cell Biol. 191, 1113–1125 (2010).

    Article  CAS  Google Scholar 

  24. Wang, S. et al. Expression and functional profiling of neprilysin, insulin-degrading enzyme, and endothelin-converting enzyme in prospectively studied elderly and Alzheimer's brain. J. Neurochem. 115, 47–57 (2010).

    Article  CAS  Google Scholar 

  25. Sacktor, T.C. How does PKMζ maintain long-term memory? Nat. Rev. Neurosci. 12, 9–15 (2011).

    Article  CAS  Google Scholar 

  26. Bramham, C.R. et al. The Arc of synaptic memory. Exp. Brain Res. 200, 125–140 (2010).

    Article  Google Scholar 

  27. Lisman, J., Schulman, H. & Cline, H. The molecular basis of CaMKII function in synaptic and behavioural memory. Nat. Rev. Neurosci. 3, 175–190 (2002).

    Article  CAS  Google Scholar 

  28. Leuba, G. et al. Differential changes in synaptic proteins in the Alzheimer frontal cortex with marked increase in PSD-95 postsynaptic protein. J. Alzheimers Dis. 15, 139–151 (2008).

    Article  CAS  Google Scholar 

  29. Tsaytler, P. & Bertolotti, A. Exploiting the selectivity of protein phosphatase 1 for pharmacological intervention. FEBS J. 280, 766–770 (2013).

    Article  CAS  Google Scholar 

  30. Cullinan, S.B. et al. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol. Cell Biol. 23, 7198–7209 (2003).

    Article  CAS  Google Scholar 

  31. Hetz, C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat. Rev. Mol. Cell Biol. 13, 89–102 (2012).

    Article  CAS  Google Scholar 

  32. Zhang, P. et al. The GCN2 eIF2alpha kinase is required for adaptation to amino acid deprivation in mice. Mol. Cell Biol. 22, 6681–6688 (2002).

    Article  CAS  Google Scholar 

  33. Alberini, C. The role of protein synthesis during the labile phases of memory: revisiting the skepticism. Neurobiol. Learn. Mem. 89, 234–246 (2008).

    Article  CAS  Google Scholar 

  34. Paschen, W., Proud, C.G. & Mies, G. Shut-down of translation, a global neuronal stress response: mechanisms and pathological relevance. Curr. Pharm. Des. 13, 1887–1902 (2007).

    Article  CAS  Google Scholar 

  35. Wek, R.C. & Cavener, D.R. Translational control and the unfolded protein response. Antioxid. Redox Signal. 9, 2357–2371 (2007).

    Article  CAS  Google Scholar 

  36. Lin, M.T. & Beal, M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–795 (2006).

    Article  CAS  Google Scholar 

  37. Ma, T. & Klann, E. Amyloid β: linking synaptic plasticity failure to memory disruption in Alzheimer's disease. J. Neurochem. 120 (suppl. 1): 140–148 (2012).

    Article  CAS  Google Scholar 

  38. Klann, E. & Richter, J.D. Translational control of synaptic plasticity and learning and memory. in Translational Control in Biology and Medicine (eds., Mathews, M.B., Sonenberg, N. & Hershey, J.W.B.) 485–506 (Cold Spring Harbor Laboratory Press, 2007).

  39. Sidrauski, C. et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife 2, e00498 (2013).

    Article  Google Scholar 

  40. Zhan, K., Narasimhan, J. & Wek, R.C. Differential activation of eIF2 kinases in response to cellular stresses in Schizosaccharomyces pombe. Genetics 168, 1867–1875 (2004).

    Article  CAS  Google Scholar 

  41. Hamanaka, R.B., Bennett, B.S., Cullinan, S.B. & Diehl, J.A. PERK and GCN2 contribute to eIF2alpha phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway. Mol. Biol. Cell 16, 5493–5501 (2005).

    Article  CAS  Google Scholar 

  42. Jiang, H.-Y. et al. Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. Mol. Cell Biol. 24, 1365–1377 (2004).

    Article  CAS  Google Scholar 

  43. Moreno, J.A. et al. Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature 485, 507–511 (2012).

    Article  CAS  Google Scholar 

  44. Tsien, J.Z. et al. Subregion- and cell type-restricted gene knockout in mouse brain. Cell 87, 1317–1326 (1996).

    Article  CAS  Google Scholar 

  45. Banko, J.L. et al. The translation repressor 4E–BP2 is critical for eIF4F complex formation, synaptic plasticity, and memory in the hippocampus. J. Neurosci. 25, 9581–9590 (2005).

    Article  CAS  Google Scholar 

  46. Ma, T. et al. Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease. PLoS ONE 5, e12845 (2010).

    Article  Google Scholar 

  47. Bonda, D.J. et al. Indoleamine 2,3-dioxygenase and 3-hydroxykynurenine modifications are found in the neuropathology of Alzheimer's disease. Redox Rep. 15, 161–168 (2010).

    Article  CAS  Google Scholar 

  48. Barker, G.R.I. & Warburton, E.C. When is the hippocampus involved in recognition memory? J. Neurosci. 31, 10721–10731 (2011).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the late Dr. Mark A. Smith (Case Western Reserve University) for providing postmortem Alzheimer's disease brain samples, R.C. Wek (Indiana University School of Medicine) for providing the ATF4 antibody, C.A. Hoeffer for help with the design of the mouse breeding, H. Bowling and M.V. Chao (New York University School of Medicine) for providing primary cultured neurons, E. Santini for advice on the statistical analyses for the mouse behavioral tests, Y. Chen for technical help, M. Dorsey for keeping colonies of transgenic mice, and all members of the Klann laboratory for comments on the manuscript. This work was supported by US National Institutes of Health grants NS034007 and NS047834, and Alzheimer's Association Investigator grant to E.K.

Author information

Authors and Affiliations

Authors

Contributions

T.M. did the majority of the experimental work and data analysis. M.A.T. performed western blots and immunohistochemistry on postmortem human tissue. A.J.W. did object location test scoring, performed western blots for the GCN2-deficient mice and genotyped mice. C.B. and E.G. performed western blots for the PKR mutant mice. P.P. provided puromycin antibody. P.P. and E.G. were involved in the experimental design. D.R.C. provided breeders of PERK conditional mutant and GCN2-deficient mice. E.K. directed and supervised the project. T.M. and E.K. designed the experiments and wrote the paper. All authors contributed to the analysis of data, discussion of the results and the final draft of the paper.

Corresponding author

Correspondence to Eric Klann.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 1309 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ma, T., Trinh, M., Wexler, A. et al. Suppression of eIF2α kinases alleviates Alzheimer's disease–related plasticity and memory deficits. Nat Neurosci 16, 1299–1305 (2013). https://doi.org/10.1038/nn.3486

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.3486

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing