Related Experiment Video

Updated: Feb 27, 2026

Using Enzyme-based Biosensors to Measure Tonic and Phasic Glutamate in Alzheimer's Mouse Models
10:46

Using Enzyme-based Biosensors to Measure Tonic and Phasic Glutamate in Alzheimer's Mouse Models

Published on: May 3, 2017

11.8K

Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer's Mouse Phenotypes

Laura T Haas1, Santiago V Salazar2, Levi M Smith2

  • 1Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, CT 06520, USA; Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, 72074 Tübingen, Germany.

Cell Reports
|July 7, 2017
PubMed

Insights

Silent allosteric modulators targeting metabotropic glutamate receptor 5 (mGluR5) show promise for Alzheimer's disease (AD). This approach separates mGluR5

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Metabotropic glutamate receptor 5 (mGluR5) is implicated in Alzheimer's disease (AD) pathology.
  • The precise role of mGluR5 in AD pathogenesis, particularly its interaction with amyloid-β oligomers (Aβo), requires further elucidation.

Purpose of the Study:

  • To investigate whether the role of mGluR5 in AD is dependent on glutamate signaling.
  • To differentiate the physiological functions of mGluR5 from its pathological involvement in Aβo-mediated neurotoxicity.

Main Methods:

  • Utilized a potent mGluR5 silent allosteric modulator (SAM, BMS-984923) to selectively target mGluR5.
  • Assessed the impact of SAM on mGluR5 interaction with cellular prion protein (PrPC) bound to Aβo.
  • Evaluated SAM's efficacy in preventing Aβo-induced signaling in brain slices and an AD transgenic mouse model (APPswe/PS1ΔE9).

Main Results:

  • The SAM selectively reduced mGluR5 interaction with Aβo-bound PrPC without altering basal glutamate signaling.
  • SAM treatment prevented Aβo-induced signal transduction in brain slices and in the APPswe/PS1ΔE9 mouse model.
  • Four weeks of SAM treatment rescued memory deficits and synaptic depletion in APPswe/PS1ΔE9 mice.

Conclusions:

  • The pathological role of mGluR5 in Aβo-dependent AD phenotypes is distinct from its role in glutamate signaling.
  • Silent allosteric modulation of mGluR5 represents a promising therapeutic strategy for Alzheimer's disease.
  • mGluR5 SAMs offer potential as disease-modifying AD interventions with a broad therapeutic window.
Keywords:
Alzheimeramyloid βmGluR5metabotropic glutamate receptor 5oligomerprion proteinsilent allosteric modulatortransgenic mouse

More Related Videos

HSV-Mediated Transgene Expression of Chimeric Constructs to Study Behavioral Function of GPCR Heteromers in Mice07:30

HSV-Mediated Transgene Expression of Chimeric Constructs to Study Behavioral Function of GPCR Heteromers in Mice

Published on: July 9, 2016

7.7K
Single Synapse Indicators of Glutamate Release and Uptake in Acute Brain Slices from Normal and Huntington Mice08:27

Single Synapse Indicators of Glutamate Release and Uptake in Acute Brain Slices from Normal and Huntington Mice

Published on: March 11, 2020

6.7K

Related Concept Videos

Ligand-Gated Ion Channel Receptor: Gating Mechanism01:30

Ligand-Gated Ion Channel Receptor: Gating Mechanism

Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
4.4K
Allosteric Regulation01:08

Allosteric Regulation

Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
63.8K