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

På svenska

Author

  • Brenna C. Beckelman
  • Stephen Day
  • Xueyan Zhou
  • Maggie Donohue
  • Gunnar K. Gouras
  • Eric Klann
  • C. Dirk Keene
  • Tao Ma

Summary, in English

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.

Publishing year

2016-09-06

Language

English

Pages

669-678

Publication/Series

Journal of Alzheimer's Disease

Volume

54

Issue

2

Document type

Journal article

Publisher

IOS Press

Topic

  • Neurosciences

Keywords

  • Alzheimer's disease
  • elongation factor
  • long-term potentiation
  • mTOR
  • protein synthesis
  • synaptic plasticity

Status

Published

Research group

  • Experimental Dementia Research

ISBN/ISSN/Other

  • ISSN: 1387-2877