# Exploring the modulation of synaptic/extrasynaptic NMDAR balance as a novel therapeutic strategy in Alzheimer's disease and other neurodegenerations

> **NIH NIH R01** · DREXEL UNIVERSITY · 2022 · $468,685

## Abstract

Excitotoxicity is defined as the deterioration of neuronal function/structure caused by excessive glutamatergic
stimulation. It is a shared major pathological hallmark in many neurodegenerative diseases (ND), including
Alzheimer’s disease (AD), Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Excitotoxicity is
mostly mediated by the activation of the NMDA-type of glutamate receptors (NMDARs). However, the NMDAR
function is indispensable for normal neuronal function. This conundrum is explained by the fact that NMDARs
are segregated in two populations: synaptic (sNMDARs) and extrasynaptic (exNMDARs). While sNMDARs are
linked to pro-survival signaling, over-activation of exNMDARs triggers excitotoxicity. Therefore, exNMDAR are
obvious pharmacological targets in a broad range of ND and, in fact, blocking NMDAR activity strongly
ameliorates cognitive defects in AD and HD mouse models. However, selective inhibition of exNMDARs is
challenging, and the vast majority of NMDAR antagonists have failed in clinic due to side effects mediated by
sNMDAR blockade. We propose to test a novel therapeutic strategy based on the fact that s- and exNMDARs
are not independent populations. On the contrary, s- and exNMDARs pools are physiologically connected via
lateral diffusion. We hypothesize that shifting the s/exNMDAR balance towards synaptic expression would be
beneficial two-folds (i) promoting survival cascades (sNMDAR-mediated) and (ii) decreasing pro-death signaling
(exNMDAR-mediated). We are ideally suited to test this strategy because we have previously identified several
of the mechanisms controlling s/exNMDAR balance. Those include different protein interactions with the
GluN2B-subunit of NMDARs and a particular phosphorylation on GluN2B (at S1480) that promotes sNMDAR
clearance and receptor stabilization at extrasynaptic sites. The goal of this proposal is to validate the proof-of-principle that reducing excitotoxicity by preventing sNMDAR clearance and/or promoting exNMDAR reinsertion
into synaptic sites is an effective therapeutic strategy in ND. In Aim 1, we will evaluate novel molecular tools to
modulate s/exNMDAR balance in culture and in vivo, including (i) small interfering peptides (sIPs) and (ii)
pharmacology to modulate GluN2B phosphorylation. Our study includes the repurposing of an anti-tumoral drug
currently in phase 1/2 of clinical trial. Also, we will use proteomics to compare the posttranslational modification
profile of s- vs. exNMDARs, aiming to identify novel mechanisms regulating the balance. In Aim 2, we will
evaluate the suitability of this strategy as a common therapeutic strategy in ND. First, we will test the efficacy of
our tools in ameliorating excitotoxicity-mediated pathological outcomes in several models of AD, both in culture
and in vivo. Finally, we will use our strategy in primary cultures from models of HD (associated by excitotoxicity)
and Parkinson’s disease (excitotoxicity is not a primary pathomecha...

## Key facts

- **NIH application ID:** 10427332
- **Project number:** 7R01AG069266-03
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** Antonio Sanz-Clemente
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $468,685
- **Award type:** 7
- **Project period:** 2022-07-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427332

## Citation

> US National Institutes of Health, RePORTER application 10427332, Exploring the modulation of synaptic/extrasynaptic NMDAR balance as a novel therapeutic strategy in Alzheimer's disease and other neurodegenerations (7R01AG069266-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10427332. Licensed CC0.

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