| First Author | Haas LT | Year | 2017 |
| Journal | Cell Rep | Volume | 20 |
| Issue | 1 | Pages | 76-88 |
| PubMed ID | 28683325 | Mgi Jnum | J:254503 |
| Mgi Id | MGI:6103915 | Doi | 10.1016/j.celrep.2017.06.023 |
| Citation | Haas LT, et al. (2017) Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer's Mouse Phenotypes. Cell Rep 20(1):76-88 |
| abstractText | 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-beta oligomer (Abetao) action. Binding of the SAM to mGluR5 does not change glutamate signaling but strongly reduces mGluR5 interaction with cellular prion protein (PrP(C)) bound to Abetao. The SAM compound prevents Abetao-induced signal transduction in brain slices and in an AD transgenic mouse model, the APPswe/PS1DeltaE9 strain. Critically, 4 weeks of SAM treatment rescues memory deficits and synaptic depletion in the APPswe/PS1DeltaE9 transgenic mouse brain. Our data show that mGluR5''s role in Abetao-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. |
