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

NEUROBIOLOGY OF AGING

卷:41

Article

Yang, Wenzhong¹  Zhou, Xueyan¹  Zimmermann, Helena R.¹  Cavener, Douglas R.²  Klann, Eric³  Ma, Tao^1,4,5 

[1] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med Gerontol & Geriatr Med, Sticht Ctr Aging, Med Ctr Blvd, Winston Salem, NC 27157 USA

[2] Penn State Univ, Dept Biol, University Pk, PA 16802 USA

[3] NYU, Ctr Neural Sci, New York, NY 10003 USA

[4] Wake Forest Univ, Bowman Gray Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC 27103 USA

[5] Wake Forest Univ, Bowman Gray Sch Med, Dept Neurobiol & Anat, Winston Salem, NC USA

关键词: Alzheimer's disease;    mGluR-LTD;    PERK;    eIF2 alpha;    Protein synthesis;    Synaptic plasticity;   

DOI  :  10.1016/j.neurobiolaging.2016.02.005

来源: Elsevier

【 摘 要 】

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 eIF2 alpha. These data are congruent with recent evidence that inhibition of eIF2 alpha 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. (C) 2016 Elsevier Inc. All rights reserved.

【 授权许可】

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