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

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-? oligomer (A?o) action. Binding of the SAM to mGluR5 does not change glutamate signaling but strongly reduces mGluR5 interaction with cellular prion protein (PrPC) bound to A?o. The SAM compound prevents A?o-induced signal transduction in brain slices and in an AD transgenic mouse model, the APPswe/PS1?E9 strain. Critically, 4 weeks of SAM treatment rescues memory deficits and synaptic depletion in the APPswe/PS1?E9 transgenic mouse brain. Our data show that mGluR5's role in A?o-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.

SUBMITTER: Haas LT 

PROVIDER: S-EPMC5547898 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature