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

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 (PrPC) 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. [Display omitted] •A potent mGluR5 SAM blocks Aβo/PrPC but not glutamate signaling•The mGluR5 SAM rescues age-dependent memory loss in an AD mouse model•Synapse density is restored by mGluR5 SAM treatment over 4 weeks•mGluR5 SAM reveals a glutamate-independent AD role with a wide therapeutic index Haas et al. investigate the role of mGluR5 in Alzheimer’s disease. They describe a compound that blocks the action of amyloid β through this receptor but preserves glutamate signaling. This amyloid-selective blocker rescues transgenic mouse models of Alzheimer’s disease and, by sparing glutamate signaling, avoids the side effects of typical mGluR5 antagonists.