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

Tao Ma, Mimi A. Trinh, Alyse J. Wexler, Clarisse Bourbon, Evelina Gatti, Philippe Pierre, Douglas R. Cavener, Eric Klann

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1299-1305
Number of pages7
JournalNature Neuroscience
Volume16
Issue number9
DOIs
StatePublished - Sep 2013

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Eukaryotic Initiation Factor-2
Memory Disorders
Alzheimer Disease
Phosphotransferases
Neuronal Plasticity
Phosphorylation
Long-Term Memory
Brain Diseases
Proteins
Mutation
Therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)

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Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits. / Ma, Tao; Trinh, Mimi A.; Wexler, Alyse J.; Bourbon, Clarisse; Gatti, Evelina; Pierre, Philippe; Cavener, Douglas R.; Klann, Eric.

In: Nature Neuroscience, Vol. 16, No. 9, 09.2013, p. 1299-1305.

Research output: Contribution to journalArticle

Ma, T, Trinh, MA, Wexler, AJ, Bourbon, C, Gatti, E, Pierre, P, Cavener, DR & Klann, E 2013, 'Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits', Nature Neuroscience, vol. 16, no. 9, pp. 1299-1305. https://doi.org/10.1038/nn.3486
Ma, Tao ; Trinh, Mimi A. ; Wexler, Alyse J. ; Bourbon, Clarisse ; Gatti, Evelina ; Pierre, Philippe ; Cavener, Douglas R. ; Klann, Eric. / Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits. In: Nature Neuroscience. 2013 ; Vol. 16, No. 9. pp. 1299-1305.
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