Alzheimer?s disease (AD) is the most common form of dementia in the elderly and is poised to become a new epidemic in the 21st century. There is currently no cure for AD or means to stop its progression. Moreover, the basic molecular mechanisms responsible for AD remain elusive. Many essential cellular processes are affected in AD, including impairment of de novo protein synthesis (mRNA translation). Protein synthesis is required for long-term memory formation; several aspects of translation are dysregulated in AD. Recent evidence shows eukaryotic elongation factor 2 (eEF2) activity is downregulated in the brains of AD model mice and human AD patients. During translation, eEF2 mediates the translocation of aminoacyl-tRNA from the ribosomal A- to P-site. Phosphorylation of eEF2 by its only known kinase, eEF2 kinase (eEF2K), blocks eEF2 activity and suppresses general protein synthesis. eEF2 is hyperphosphorylated in post mortem human AD brains and the hippocampi of AD model mice. Furthermore, the signaling pathways that regulate eEF2K have been implicated in AD pathogenesis. Thus, the objective of this proposal is to determine whether inhibition of eEF2K activity (and subsequent upregulation of eEF2) alleviates AD-associated deficits in protein synthesis and memory formation. This project will utilize a genetic approach in which eEF2K activity is downregulated in Tg19959 AD model mice. Using behavioral, electrophysiological, and biochemical methods, the experiments proposed here will 1) elucidate whether suppression of eEF2K activity rescues memory deficits in AD model mice; 2) determine whether inhibition of eEF2K can alleviate AD-associated synaptic plasticity impairments; and 3) establish whether reduction in eEF2 phosphorylation improves AD pathology, including brain amyloid deposition and tau hyperphosphorylation. The experiments proposed here will help elucidate a novel mechanism for AD pathophysiology, potentially shedding light on novel therapeutic targets.

Public Health Relevance

There is currently no treatment to cure or prevent Alzheimer?s disease, a devastating progressive form of memory loss common in the elderly. As the disease progresses, neurons loose their ability to synthesize new proteins?molecules essential for maintaining the health and function of the brain. The current project will determine whether boosting protein synthesis in neurons relieves cognitive dysfunction in Alzheimer?s disease model mice and potentially reveal a novel target for drug interventions.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F01A-F (20)L)
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Yang, Austin Jyan-Yu
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Wake Forest University Health Sciences
Internal Medicine/Medicine
Schools of Medicine
United States
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Zimmermann, Helena R; Yang, Wenzhong; Beckelman, Brenna C et al. (2018) Genetic removal of eIF2? kinase PERK in mice enables hippocampal L-LTP independent of mTORC1 activity. J Neurochem 146:133-144