# The role of NMDA receptor subunit GluN3A in age and Alzheimer's disease-related dementia

> **NIH NIH R21** · EMORY UNIVERSITY · 2022 · $195,625

## Abstract

Summary
 Dementia and Alzheimer’s disease (AD) affect hundreds of millions of people in the US and worldwide,
after several decades of intensive investigations clinical treatments of these age-related disorders are still very
limited. Previous investigations using animal models established on the amyloid beta (Aβ) and Tau hypothesis
have helped to gain extensive knowledge on the pathological features and progression of AD related dementia.
Unfortunately, clinical trials directly targeting Aβ and Tau pathology have so far failed clinical translation. On
the other hand, hyperactivation of N-Methyl-D-aspartate receptors (NMDARs) has been identified as a key
mechanism contributing to AD pathology and pathogenesis. The NMDAR antagonist memantine is one of few
treatments showing some therapeutic benefits for moderate/severe AD and dementia patients. In fact,
pharmacological suppression of glutamatergic activities has become an important strategy in postponing Aβ-
induced neuronal damage and AD progression. The research in NMDAR regulations, however, has been
heavily focused on the NMDAR subunits GluN1 and GluN2, there is no information about the role of GluN3A in
AD related mechanism. As a unique inhibitory subunit of NMDARs, GluN3 keeps the tonic NMDAR activity and
chronic Ca2+ homeostasis within the physiological range. Deletion of GluN3A in the knockout (KO) mouse
resulted in enhanced neuronal cell death and anxiety behaviors at adult ages. Our preliminary data show that
GluN3A KO mice undergo spontaneous evolvement of AD-like pathology and cognitive deficits with aging,
which can be prevented by daily treatments of low-dose memantine initiated from the pre-onset stage. In this
R21 investigation, we will verify the pathogenic role of GluN3A in age-dependent manners. Specific Aim 1 will
characterize the pathological features of the age-dependent dementia and the relation to Alzheimer’s
disease. In GluN3A KO and WT mice of different ages, we will examine Aβ plagues, NFT, phosphorylation of
Tau protein, synaptic structures and cell death in the hippocampus and cortex. Inflammatory reactions
including reactive astrocytes, microglia/microphage, and inflammatory factors will be measure. Specific Aim 2
will delineate the critical time window for the role of GluN3A in progression of AD-associated
pathophysiology. We will perform loss-of-function experiments of conditional GluN3A knockout at different
ages to understand whether there is a critical time point for initiating the age-dependent evolvement of
dementia and AD pathophysiology. This R21 investigation is the first effort in revealing a regulatory/pathogenic
role of the NMDAR subunit GluN3A in age-related dementia and possibly a sporadic AD mouse model. This
exploratory study will allow us to develop an evidence-based systematic investigation on the GluN3A-regulated
mechanism of dementia and AD pathology. Our ultimate goal is to identify GluN3A as a novel therapeutic
target and develop early genetic a...

## Key facts

- **NIH application ID:** 10491045
- **Project number:** 5R21AG067473-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Shan P. Yu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $195,625
- **Award type:** 5
- **Project period:** 2021-09-30 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10491045

## Citation

> US National Institutes of Health, RePORTER application 10491045, The role of NMDA receptor subunit GluN3A in age and Alzheimer's disease-related dementia (5R21AG067473-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10491045. Licensed CC0.

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