Elucidating a role for eEF2 phosphorylation in Alzheimer's Disease pathogenesis.

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Project Summary/Abstract 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.