title: Dysregulation of Elongation Factor 1A Expression is Correlated with Synaptic Plasticity Impairments in Alzheimer's Disease.
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, 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.
authors: Sticht Center on Aging, Department of Internal Medicine-Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors: Brenna C
authors: BC
authors: Beckelman
authors: Sticht Center on Aging, Department of Internal Medicine-Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors: Stephen
authors: S
authors: Day
authors: Sticht Center on Aging, Department of Internal Medicine-Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors: Xueyan
authors: X
authors: Zhou
authors: Center for Neural Science, New York University, New York, NY, USA.
authors: Maggie
authors: M
authors: Donohue
authors: Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors: Gunnar K
authors: GK
authors: Gouras
authors: Center for Neural Science, New York University, New York, NY, USA.
authors: Eric
authors: E
authors: Klann
authors: Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.
authors: C Dirk
authors: CD
authors: Keene
authors: Sticht Center on Aging, Department of Internal Medicine-Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.|Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.|Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors: Tao
authors: T
authors: Ma
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D005260:Female; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology*; D009924:Organ Culture Techniques; D020648:Peptide Elongation Factor 1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D020648:Peptide Elongation Factor 1
keywords: Alzheimer’s disease; elongation factor; long-term potentiation; mTOR; protein synthesis; synaptic plasticity