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

Abstract

SUMMARY 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/PS1 ΔE9 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.

Anti‐PrPC antibody rescues cognition and synapses in transgenic alzheimer mice

“…The interaction of Aßo with PrP C engages mGluR5 to cause synaptic dysfunction and loss . We sought to test whether AZ59 would prevent mGluR5 interactions driven by Aßo.…”

“…Mice were tested for novel object recognition as described . Spatial learning and memory were analyzed using the Morris water maze as described . Throughout behavioral testing, the experimenter was unaware of genotype and treatment.…”

“…Cellular Prion Protein (PrP C ), a glycol‐phosphatidyl‐inositol‐anchored protein highly expressed in neurons, acts as a high‐affinity receptor for Aβo and is required for learning, memory, and synaptic deficits in APP/PS1 and Tg2576 mice, though not in all AD models (reviewed in). Downstream components of the Aβo‐PrP C pathway have been elucidated and successfully targeted in APP/PS1 mice, including mGluR5, Fyn kinase, and the human AD risk gene product, Pyk2 kinase . Interventions targeting PrP C , Fyn, or mGluR5 do not alter Aβ levels, demonstrating that the Aβo‐PrP C pathway can be beneficially modified without altering plaque load per se .…”

Aβ oligomers induce sex-selective differences in mGluR5 pharmacology and pathophysiological signaling in Alzheimer mice

“…Genetic silencing has clearly demonstrated a contributory role of mGluR5 in AD pathogenesis, specifically Aβ-related pathology in male APPswe/PS1ΔE9 mice (25). Furthermore, while both negative and silent mGluR5 modulators rescue AD mouse behavioral phenotypes, only mGluR5 NAMs treatment mitigated Aβ pathology in a preclinical male APPswe/PS1ΔE9 and 3xTg-AD mouse models of AD (20,23,34). However, gender-specific responses to therapies have been reported in many neurological diseases including AD that further complicated the process of drug discovery (9)(10)(11).…”

Reversible silencing of endogenous receptors in intact brain tissue using two-photon pharmacology

“…Currently, the best available option is alloswitch and its analog compounds, which are freely-diffusible allosteric modulators of metabotropic glutamate 5 (mGlu 5 ) receptors 16,28 . These receptors are important modulators of neurotransmission and synaptic plasticity 29 , and are involved in several neurological conditions 30,31,32,33,34,35 . Alloswitch and its analogs are subtype-selective, allosteric ligands with nanomolar activity that can turn on and off endogenous mGlu 5 receptors in vivo.…”