Impaired Eukaryotic Elongation Factor 1A Expression in Alzheimer's Disease

Abstract

Background/aims: Recent studies have indicated a link between the impaired capacity of de novo protein synthesis and neurodegenerative diseases including Alzheimer's disease (AD). Moreover, it has been established that eukaryotic elongation factor 1A (eEF1A) plays a critical role in maintaining long-term synaptic plasticity, a cellular model for learning and memory. The aim of the present study is to determine whether brain eEF1A protein levels are dysregulated in brain tissue from AD patients compared with controls.

Methods: Postmortem human brain samples collected from patients clinically diagnosed as AD, and from age-matched healthy controls, were utilized for this study. Both Western blot and immunohistochemistry approaches were utilized to investigate the potential alteration of eEF1A protein levels by using a specific antibody.

Results: Our data demonstrate that eEF1A expression is reduced in AD patients in the hippocampus, but not in the cerebellum or midfrontal gyrus. Furthermore, immunohistochemical experiments reveal that neuronal eEF1A reduction in the AD hippocampus is localized to the CA1 and dentate gyrus, but not to the CA3.

Conclusion: Dysregulation of eEF1A and its associated signaling pathways might represent novel molecular mechanisms underlying AD pathogenesis. Further investigation is necessary to determine whether eEF1A is a viable therapeutic target for AD and other cognitive syndromes.

Figure 1. Hippocampal levels of eEF1A are diminished in AD cases compared to age-matched controls

(A) Representative Western blot shows reduced hippocampal eEF1A levels in AD patients (AD), compared to age-matched controls (CT). Cerebellum and midfrontal gyrus levels are similar in AD and control samples. (B) Cumulative data based on densitometric analysis for eEF1A Western blot experiments (n=10) are shown in bar graph. Levels of eEF1A are significantly decreased in hippocampi of AD patients compared to those of age-matched controls. Independent unpaired t-test, **p<0.01.

Figure 2. Hippocampal neuronal eEF1A levels are reduced in human AD patients

(A) Immunohistochemistry with Aβ antibody (6E10) demonstrates abundant hippocampal “plaques” involving hilus, CA fields, and dentate gyrus of AD patients (AD), whereas controls (CT) have very little plaque deposition. Representative images are shown for 4× (scale bar 1 mm) and 20× (scale bar 200 µm) magnification. (B) Compared with controls, patients with AD have decreased eEF1A immunostaining in CA1 pyramidal neurons. (C) In hilar neurons (CA4) of the dentate gyrus, AD patients also displaya pronounced reduction in eEF1A levels. (D) Levels of eEF1A immunostaining in CA3 pyramidal neurons in AD patients are not different from controls. For (B), (C), and (D), representative images are shown for 20× (scale bar 200 µm) and 63× (scale bar 50 µm) magnification. Images shown represent results from four independent experiments.