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.

Genetic reduction of eEF2 kinase alleviates pathophysiology in Alzheimer’s disease model mice

“…Suppression of eIF2α phosphorylation corrected AD-associated cognitive and synaptic plasticity defects (17), indicating a crucial role of translation initiation dysregulation in AD pathogenesis. Mounting evidence suggests an important role for elongation regulation in cognition, with recent studies linking dysregulation of elongation factors with AD pathophysiology (15,(44)(45)(46)(47). Of note, a recent study showed a connection between eIF2 signaling and eEF2 phosphorylation in neurons (48).…”

“…Breeders of Tg19959 AD model mice were a gift from George Western blots for postmortem human tissue. Hippocampal tissue from AD, FTD, and LBD patients and their respective age-matched controls was sonicated as previously described (45). Samples containing equal amounts of protein lysate were loaded on 4%-12% Trisglycine SDS-PAGE gels (Bio-Rad, catalog 4561023) for standard gel electrophoresis.…”

“…Western blots for mouse tissue. Mouse hippocampal tissue was flash-frozen on dry ice and sonicated as previously described in lysis buffer with protease and phosphatase inhibitors (45). Samples containing equal amounts of protein lysate were loaded on 4%-12% Tris-glycine SDS-PAGE (Bio-Rad) gels for standard gel electropho-randomly among 4 locations.…”

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

“…Several studies have observed decreased expression of eEF1A and eEF2 in the brains of PD and AD patients, as well as in mouse models of these diseases; however, the role of elongation in the pathogenesis of these disorders remains unclear (Beckelman et al, 2016a, 2016b, Garcia-Esparcia et al, 2015, 2017; Hernández-Ortega et al, 2016; Li et al, 2005). A better understanding of the importance of these factors in disease is gained when we turn to genetic models and patients with mutations in these genes themselves.…”

Acute and Chronic Molecular Signatures and Associated Symptoms of Blast Exposure in Military Breachers

“…Some of these loci and genes in related pathways have been previously implicated in responses to cellular stress, neurodegeneration, and TBI. [35][36][37][38] Of note, ubiquitin proteins have been implicated in TBI and neurodegenerative disease, and the ubiquitin C-terminal hydrolase-L1 (UCH-L1) has been FDA approved as a robust blood-based biomarker for acute mild brain injury. 39 Blast associated physiological and psychological symptoms linked to DNA methylation and transcriptional changes.…”