# Mechanism of Gp1 mGluR-dependent translation and plasticity

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2022 · $386,298

## Abstract

PROJECT SUMMARY/ABSTRACT
 Extensive studies have demonstrated that cellular stress and the subsequent stress response, such as
global translational suppression, are exaggerated in amyloid beta (Aβ)–associated Alzheimer’s disease and that
they facilitate neurodegeneration. Alleviating the stress response has been shown to improve neuronal and
circuit functions in animal models of Aβ pathology. However, our understanding of the molecular mechanisms
underlying Aβ-induced cellular stress response is limited. Furthermore, it is also unclear whether there is any
sex-specific regulation behind those mechanisms. To address these questions, we have gathered preliminary
data that reveal an Aβ-induced up-regulation of fragile X mental retardation protein (FMRP) and the FMRP-
dependent phosphorylation of eukaryotic translation elongation factor 2 (eEF2) and subsequent translational
suppression. Remarkably, our data also suggest that these mechanisms potentially occur only in female but not
in male mice in an Aβ-pathology mouse model. We therefore hypothesize that elevated FMRP induced by Aβ
contributes to exaggerated translational suppression and neurodegeneration, particularly in females. In Aim 1,
we propose to characterize, as well as reduce, Aβ-associated eEF2 phosphorylation to ameliorate translational
suppression in primary neurons in vitro. In Aim 2, we propose to study sex-specific regulation of FMRP and
translational suppression in Aβ pathology in vivo. We also propose to genetically inhibit FMRP to ameliorate Aβ-
induced neurodegeneration in mice in vivo. This supplemental research is within the scope of the Aim 3 of the
parent award in which the FMRP-dependent regulation of global translational suppression and synaptic plasticity
are being studied through phosphorylation signaling. Through the research of FMRP in Alzheimer’s disease, we
expect that our results will (1) elucidate a novel mechanism by which accumulation of Aβ leads to translational
suppression, (2) uncover a sex-specific regulation in translational suppression in Aβ pathology, and (3) suggest
novel therapeutic targets for ameliorating exaggerated cellular stress response and neurodegeneration in
Alzheimer’s disease. Building on existing tools and substantial knowledge of FMRP, our research has the
potential to quickly open new avenues for the future study of Alzheimer’s disease–associated cognitive decline
and memory impairment.

## Key facts

- **NIH application ID:** 10469161
- **Project number:** 3R01MH124827-02S1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Nien-Pei Tsai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $386,298
- **Award type:** 3
- **Project period:** 2020-12-01 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469161

## Citation

> US National Institutes of Health, RePORTER application 10469161, Mechanism of Gp1 mGluR-dependent translation and plasticity (3R01MH124827-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10469161. Licensed CC0.

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