Repression of the eIF2α kinase PERK alleviates mGluR-LTD impairments in a mouse model of Alzheimer's disease

Wenzhong Yang, Xueyan Zhou, Helena R. Zimmermann, Douglas R. Cavener, Eric Klann, Tao Ma

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Mounting evidence indicates that impairments of synaptic efficacy and/or plasticity may be a key step in the development of Alzheimer's disease (AD) pathophysiology. Among the 2 major forms of synaptic plasticity, long-term potentiation and long-term depression (LTD), much less is known about how LTD is regulated in AD and its molecular mechanisms. Recent studies indicate that metabotropic glutamate receptor 5 (mGluR5) may function as a receptor and/or co-receptor for amyloid beta. Herein, we examined mGluR-LTD in hippocampal slices from aged APP/PS1 mutant mice that model AD. Our findings demonstrate that mGluR-LTD is blocked in APP/PS1 mice, and that the mGluR-LTD failure is reversed by either genetically or pharmacologically suppressing the activity of PERK, a kinase for the mRNA translation factor eIF2α. These data are congruent with recent evidence that inhibition of eIF2α phosphorylation via PERK suppression and reversal of de novo protein synthesis deficits can mitigate cognitive deficits in neurodegenerative diseases. Together with reports indicating that mGluR5 may mediate amyloid beta synaptotoxicity, our findings offer insights into novel therapeutic targets for AD and other cognitive syndromes.

Original languageEnglish (US)
Pages (from-to)19-24
Number of pages6
JournalNeurobiology of Aging
Volume41
DOIs
StatePublished - May 1 2016

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Alzheimer Disease
Depression
Metabotropic Glutamate 5 Receptor
Amyloid
Neuronal Plasticity
Long-Term Potentiation
Protein Biosynthesis
Neurodegenerative Diseases
Phosphorylation
PERK kinase
Proteins
Therapeutics

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Yang, Wenzhong ; Zhou, Xueyan ; Zimmermann, Helena R. ; Cavener, Douglas R. ; Klann, Eric ; Ma, Tao. / Repression of the eIF2α kinase PERK alleviates mGluR-LTD impairments in a mouse model of Alzheimer's disease. In: Neurobiology of Aging. 2016 ; Vol. 41. pp. 19-24.
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Repression of the eIF2α kinase PERK alleviates mGluR-LTD impairments in a mouse model of Alzheimer's disease. / Yang, Wenzhong; Zhou, Xueyan; Zimmermann, Helena R.; Cavener, Douglas R.; Klann, Eric; Ma, Tao.

In: Neurobiology of Aging, Vol. 41, 01.05.2016, p. 19-24.

Research output: Contribution to journalArticle

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