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

In English

Författare

  • 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.

Publiceringsår

2016-09-06

Språk

Engelska

Sidor

669-678

Publikation/Tidskrift/Serie

Journal of Alzheimer's Disease

Volym

54

Issue

2

Dokumenttyp

Artikel i tidskrift

Förlag

IOS Press

Ämne

  • Neurosciences

Nyckelord

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

Status

Published

Forskningsgrupp

  • Experimental Dementia Research

ISBN/ISSN/Övrigt

  • ISSN: 1387-2877