A Silent Allosteric Modulator

Abstract

Deterioration in cognitive dysfunction in Alzheimer’s disease (AD) patients is associated with microglia-mediated synaptic destruction. Using AD mouse models Spurrier and colleagues discerned the function of the metabotropic glutamate receptor 5 (mGluR5) on synaptic loss and demonstrated that a silent allosteric modulator (SAM) of mGLuR5 when given through the oral route successfully restored synaptic density and reduced phosphorylated TAU accumulation. The treatment in AD mice with SAM reversed the induced changes as a result of altered gene expression and blocked the synaptic confinement of the C1q complement protein. The findings of this study suggest that targeting mGluR5 with SAMs could be a powerful strategy for restricting AD-related synaptic loss. Sci. Transl. Med.14, eabi8593 (2022).