Role of eEF2 Hyper-phosphorylation in Alzheimer’s-Associated Synaptic Failure and Memory Deficits

The basic causes underlying the cognitive deterioration in Alzheimer’s disease (AD) and other dementias remain elusive, which hampers the development of any effective therapies. This project will shed light on whether new proteins synthesized in association with a cellular signaling factor (eEF2K/eEF2 signaling) play a role in AD pathogenesis This work could inform future identification of novel diagnostic markers and therapeutic targets for AD and related cognitive syndromes.

The goal of our project is to understand the detailed mechanisms underlying AD, and particularly the role of a messenger RNA (mRNA) known as translational factor elongation factor 2 (eEF2) in AD-associated dementia syndrome. There are three aims for this project. For Aim 1, we seek to determine whether restoration of normal eEF2 activity rescues AD-associated impairments in synaptic plasticity, in a cellular model of learning and memory. In Aim 2, we will investigate whether normalization of eEF2 activity improves learning and memory defects in a mouse model of AD. In Aim 3, we plan to study whether AD-associated impairments of protein synthesis (mRNA translation) are alleviated by normalizing eEF2 activity. Lack of understanding of the molecular mechanisms underlying AD hinders the development of novel therapeutic targets and diagnostic biomarkers for the disease. Our work takes advantage of multiple state-of-the-art techniques and approaches, which enables us to identify, for the first time, detailed molecular mechanisms underlying protein synthesis defects associated with eEF2 signaling dysregulation in AD. Moreover, we use two sets of novel methods to measure de novo protein synthesis, which should provide important insights into the disease etiology. Completion of the project can contribute important data with regards to the signaling mechanisms underlying AD’s onset and progression.  Future studies will build on the results from this project and our other research findings on AD-related protein synthesis dysregulation to inform the eventual development of novel diagnostic markers and better therapeutic strategies for AD-related cognitive syndromes, for which no effective treatments exist.