Silent Allosteric Modulation of MGluR5 Maintains Glutamate Signaling While Rescuing Alzheimer's Mouse Phenotypes

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2017 Jul 7

PMID 28683325

Citations 55

Authors

Laura T Haas

Santiago V Salazar

Levi M Smith

Helen R Zhao

Timothy O Cox

Charlotte S Herber

Andrew P Degnan

Anand Balakrishnan

John E Macor

Charles F Albright

Stephen M Strittmatter

Affiliations

Soon will be listed here.

Abstract

Metabotropic glutamate receptor 5 (mGluR5) has been implicated in Alzheimer's disease (AD) pathology. We sought to understand whether mGluR5's role in AD requires glutamate signaling. We used a potent mGluR5 silent allosteric modulator (SAM, BMS-984923) to separate its well-known physiological role in glutamate signaling from a pathological role in mediating amyloid-β oligomer (Aβo) action. Binding of the SAM to mGluR5 does not change glutamate signaling but strongly reduces mGluR5 interaction with cellular prion protein (PrP) bound to Aβo. The SAM compound prevents Aβo-induced signal transduction in brain slices and in an AD transgenic mouse model, the APPswe/PS1ΔE9 strain. Critically, 4 weeks of SAM treatment rescues memory deficits and synaptic depletion in the APPswe/PS1ΔE9 transgenic mouse brain. Our data show that mGluR5's role in Aβo-dependent AD phenotypes is separate from its role in glutamate signaling and silent allosteric modulation of mGluR5 has promise as a disease-modifying AD intervention with a broad therapeutic window.

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