The basic cellular/molecular signaling mechanisms underlying Alzheimer?s disease (AD) pathophysiology are not well understood; this gap in knowledge is hampering our ability to find any effective therapies. Accumulating evidence indicates impaired synaptic function as a key event in AD pathogenesis. However, the molecular mechanisms underlying AD-associated synaptic dysfunction/failure remain elusive. We recently reported hyperphosphorylation of mRNA translational factor eukaryotic elongation factor 2 (eEF2) in AD brains. Phosphorylation of eEF2 by its (only known) kinase eEF2K results in repression of de novo protein synthesis, which is essential for long-lasting forms of synaptic plasticity and memory. Driven by the preliminary data, the central hypothesis to be tested in this application is that restoration of the capacity for de novo protein synthesis, via inhibition of eEF2K and thus eEF2 phosphorylation, will alleviate AD-associated synaptic failure and memory impairments.
Three specific aims have been designed to test this hypothesis.
Aim 1 seeks to determine whether restoration of normal eEF2 phosphorylation, via suppressing eEF2K activity, can rescue AD-associated impairments in hippocampal long-term synaptic plasticity.
Aim 2 is to determine whether inhibition of eEF2K activity improves learning and memory deficits in AD mouse model.
Aim 3 is to determine whether AD-associated impairments of de novo protein synthesis can be mitigated by inhibiting eEF2 kinase activity. The project proposes in-depth analyses using multiple state-of-art methods in neuroscience, including synaptic electrophysiology, confocal imaging, mouse genetics, and behavioral tests. We will also employ two new types of non-radioactive methods to assess de novo protein synthesis in brain slices: surface sensing of translation (SUnSET) and bioorthogonal noncanonical amino acid tagging (BONCAT). These novel methods will be combined with mass spectrometry/proteomics approach to reveal identities of proteins in AD brains whose synthesis is dysregulated because of abnormal eEF2K/eEF2 signaling. Findings from this project will contribute important data regarding the cellular/molecular signaling mechanisms underlying AD pathogenesis. Future studies will build on the results from this project and our other research findings on AD-related protein synthesis dysregulation to inform eventual development of novel diagnostic markers and better therapeutic strategies for AD-related cognitive syndromes, for which no effective treatments exist.
The basic causes underlying the cognitive deterioration in Alzheimer?s disease (AD) and other dementias remain elusive, which hampers development of any effective therapies. This project will help understand the role of new protein synthesis associated with eEF2K/eEF2 signaling in AD pathogenesis. This work could inform future identification of novel diagnostic markers and therapeutic targets for AD and related cognitive syndromes.
| 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 |
| Day, Stephen M; Yang, Wenzhong; Ewin, Sarah et al. (2017) Glucagon-like peptide-1 cleavage product GLP-1 (9-36) amide enhances hippocampal long-term synaptic plasticity in correlation with suppression of Kv4.2 expression and eEF2 phosphorylation. Hippocampus 27:1264-1274 |
