# mGluR5 and Phase State Dependent Synaptic Loss in Alzheimer's Disease

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $827,048

## Abstract

SUMMARY
Alzheimer’s disease (AD) afflicts 5.8 million in the USA, but there remains no disease-modifying therapy. Critical
for progression from pre-symptomatic to mild cognitive impairment (MCI) to dementia is the loss of synapses in
relevant brain regions. We seek to define the molecular basis of this synapse loss. In the previous cycle, we
demonstrated an essential role for aberrant metabotropic glutamate receptor 5 (mGluR5) activation in synapse
dysfunction, synaptic loss and memory deficits using cellular assays, brain slices and transgenic mice. Our
Preliminary studies here demonstrate that synapse loss is mGluR5-dependent in gene knock-in as well as
transgenic models, and that it can be tracked by longitudinal PET imaging. We have discovered a sub-nanomolar
potent and orally available mGluR5 silent allosteric modulator (SAM, BMS-984923) that blocks this AD process,
while preserving physiological Glu signaling.
We now aim to address two key issues regarding this clinically targeted AD synapse loss pathway. Single cell
transcriptomic profiling will be utilized to understand how synaptic mGluR5 modulation interacts with diverse
molecular pathways and glial cells in AD. Single particle cryo-electron microscope studies will be employed to
understand the basis for differential mGluR5 regulation by Aßo/PrPC vs Glu, and for SAM action. Hypotheses
generated from the transcriptomic and protein studies will be tested in human iPSC-derived neurons and in
mouse gene knock-in models. To maximize relevance, signaling will be triggered by Aßo purified from human
AD brain.

## Key facts

- **NIH application ID:** 10495207
- **Project number:** 5R01AG034924-12
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** STEPHEN M STRITTMATTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $827,048
- **Award type:** 5
- **Project period:** 2010-08-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10495207

## Citation

> US National Institutes of Health, RePORTER application 10495207, mGluR5 and Phase State Dependent Synaptic Loss in Alzheimer's Disease (5R01AG034924-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10495207. Licensed CC0.

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