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

Cell Rep. 2017 Jul 5;20(1):76-88. doi: 10.1016/j.celrep.2017.06.023.

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 (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.

Keywords: Alzheimer; amyloid β; mGluR5; metabotropic glutamate receptor 5; oligomer; prion protein; silent allosteric modulator; transgenic mouse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • HEK293 Cells
  • Humans
  • Memory
  • Mice
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Phenotype
  • Presenilins / genetics
  • Prions / metabolism
  • Protein Binding
  • Receptor, Metabotropic Glutamate 5 / metabolism*
  • Synaptic Transmission / drug effects*

Substances

  • Amyloid beta-Protein Precursor
  • Neuroprotective Agents
  • Presenilins
  • Prions
  • Receptor, Metabotropic Glutamate 5