Researchers have identified a novel mechanism and potential new therapeutic target for Alzheimer's disease (AD). The findings are published in the Journal of Clinical Investigation.
Alzheimer's is characterized by profound memory loss and synaptic failure. Although the exact cause of Alzheimer's remains unclear, it is well established that maintaining memory and synaptic plasticity requires protein synthesis.
The team and others recently have shown AD-associated hyperphosphorylation of mRNA translation factor eukaryotic elongation factor 2 (eEF2K leads) to inhibition of protein synthesis. In this study they wanted to determine if suppression of eEF2K could improve protein synthesis capacity and consequently alleviate the cognitive and synaptic impairments associated with the disease.
The researchers used a genetic approach to repress the activity of eEF2K in two different Alzheimer's mouse models. They found that genetic reduction of eEF2K suppressed AD-associated eEF2 hyperphosphorylation and improved memory deficits and hippocampal long-term potentiation (LTP) impairments without altering brain amyloid β (Aβ) pathology. Furthermore, eEF2K reduction alleviated AD-associated defects in dendritic spine morphology, postsynaptic density formation, de novo protein synthesis, and dendritic polyribosome assembly. "These findings are encouraging and provide a new pathway for further research," the senior author said.
The team hopes next to test this approach in additional animal studies and eventually in human trials using small molecule inhibitors targeting eEF2K
Reducing mRNA translation factor alleviates pathophysiology in Alzheimer's disease model mice
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