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

Nature Neuroscience volume 16, pages 1299–1305 (2013)Cite this article

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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.

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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.

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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.

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Authors and Affiliations

  1. Center for Neural Science, New York University, New York, New York, USA

    Tao Ma, Mimi A Trinh, Alyse J Wexler & Eric Klann

  2. Centre d'Immunologie de Marseille-Luminy, Unité Mixte de Recherche 6102, Centre National de la Recherche Scientifique, Université de la Méditerranée, Case 906, Marseille, France

    Clarisse Bourbon, Evelina Gatti & Philippe Pierre

  3. Institut National de la Santé et de la Recherche Médicale, U1104, Marseille, France

    Clarisse Bourbon, Evelina Gatti & Philippe Pierre

  4. Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7280, Marseille, France

    Clarisse Bourbon, Evelina Gatti & Philippe Pierre

  5. Department of Biology, Pennsylvania State University, University Park, Pennsylvania, USA

    Douglas R Cavener

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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.

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Correspondence to Eric Klann.

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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

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