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Dysregulation of Elongation Factor 1A Expression is Correlated with Synaptic Plasticity Impairments in Alzheimer's Disease

Beckelman, Brenna C.; Day, Stephen; Zhou, Xueyan; Donohue, Maggie; Gouras, Gunnar K. LU ; Klann, Eric; Keene, C. Dirk and Ma, Tao (2016) In Journal of Alzheimer's Disease 54(2). p.669-678
Abstract

Synaptic dysfunction may represent an early and crucial pathophysiology in Alzheimer's disease (AD). Recent studies implicate a connection between synaptic plasticity deficits and compromised capacity of de novo protein synthesis in AD. The mRNA translational factor eukaryotic elongation factor 1A (eEF1A) is critically involved in several forms of long-lasting synaptic plasticity. By examining postmortem human brain samples, a transgenic mouse model, and application of synthetic human Aβ42 on mouse hippocampal slices, we demonstrated that eEF1A protein levels were significantly decreased in AD, particularly in the hippocampus. In contrast, brain levels of eukaryotic elongation factor 2 were unaltered in AD. Further,... (More)

Synaptic dysfunction may represent an early and crucial pathophysiology in Alzheimer's disease (AD). Recent studies implicate a connection between synaptic plasticity deficits and compromised capacity of de novo protein synthesis in AD. The mRNA translational factor eukaryotic elongation factor 1A (eEF1A) is critically involved in several forms of long-lasting synaptic plasticity. By examining postmortem human brain samples, a transgenic mouse model, and application of synthetic human Aβ42 on mouse hippocampal slices, we demonstrated that eEF1A protein levels were significantly decreased in AD, particularly in the hippocampus. In contrast, brain levels of eukaryotic elongation factor 2 were unaltered in AD. Further, upregulation of eEF1A expression by the adenylyl cyclase activator forskolin, which induces long-lasting synaptic plasticity, was blunted in hippocampal slices derived from Tg2576 AD model mice. Finally, Aβ-induced hippocampal long-term potentiation defects were alleviated by upregulation of eEF1A signaling via brain-specific knockdown of the gene encoding tuberous sclerosis 2. In summary, our findings suggest a strong correlation between the dysregulation of eEF1A synthesis and AD-associated synaptic failure. These findings provide insights into the understanding of molecular mechanisms underlying AD etiology and may aid in identification of novel biomarkers and therapeutic targets.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer's disease, elongation factor, long-term potentiation, mTOR, protein synthesis, synaptic plasticity
in
Journal of Alzheimer's Disease
volume
54
issue
2
pages
10 pages
publisher
IOS Press
external identifiers
  • Scopus:84986557839
  • WOS:000384087200021
ISSN
1387-2877
DOI
10.3233/JAD-160036
language
English
LU publication?
yes
id
174643a4-1b9b-4921-a97c-d07927240636
date added to LUP
2016-10-03 16:10:45
date last changed
2017-01-01 08:35:45
@article{174643a4-1b9b-4921-a97c-d07927240636,
  abstract     = {<p>Synaptic dysfunction may represent an early and crucial pathophysiology in Alzheimer's disease (AD). Recent studies implicate a connection between synaptic plasticity deficits and compromised capacity of de novo protein synthesis in AD. The mRNA translational factor eukaryotic elongation factor 1A (eEF1A) is critically involved in several forms of long-lasting synaptic plasticity. By examining postmortem human brain samples, a transgenic mouse model, and application of synthetic human Aβ<sub>42</sub> on mouse hippocampal slices, we demonstrated that eEF1A protein levels were significantly decreased in AD, particularly in the hippocampus. In contrast, brain levels of eukaryotic elongation factor 2 were unaltered in AD. Further, upregulation of eEF1A expression by the adenylyl cyclase activator forskolin, which induces long-lasting synaptic plasticity, was blunted in hippocampal slices derived from Tg2576 AD model mice. Finally, Aβ-induced hippocampal long-term potentiation defects were alleviated by upregulation of eEF1A signaling via brain-specific knockdown of the gene encoding tuberous sclerosis 2. In summary, our findings suggest a strong correlation between the dysregulation of eEF1A synthesis and AD-associated synaptic failure. These findings provide insights into the understanding of molecular mechanisms underlying AD etiology and may aid in identification of novel biomarkers and therapeutic targets.</p>},
  author       = {Beckelman, Brenna C. and Day, Stephen and Zhou, Xueyan and Donohue, Maggie and Gouras, Gunnar K. and Klann, Eric and Keene, C. Dirk and Ma, Tao},
  issn         = {1387-2877},
  keyword      = {Alzheimer's disease,elongation factor,long-term potentiation,mTOR,protein synthesis,synaptic plasticity},
  language     = {eng},
  month        = {09},
  number       = {2},
  pages        = {669--678},
  publisher    = {IOS Press},
  series       = {Journal of Alzheimer's Disease},
  title        = {Dysregulation of Elongation Factor 1A Expression is Correlated with Synaptic Plasticity Impairments in Alzheimer's Disease},
  url          = {http://dx.doi.org/10.3233/JAD-160036},
  volume       = {54},
  year         = {2016},
}