# Role of protein synthesis in Alzheimers disease-associated impairments of synaptic plasticity and memory

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $464,345

## Abstract

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.

## Key facts

- **NIH application ID:** 10180826
- **Project number:** 5R01AG056622-05
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Tao Ma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $464,345
- **Award type:** 5
- **Project period:** 2017-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180826

## Citation

> US National Institutes of Health, RePORTER application 10180826, Role of protein synthesis in Alzheimers disease-associated impairments of synaptic plasticity and memory (5R01AG056622-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10180826. Licensed CC0.

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