GSE171095
Reversal of Synapse Loss in Alzheimer Mouse Models by Targeting mGluR5 to Prevent Synaptic Tagging by C1q
Longitudinal PET imaging of Alzheimer models reveals synaptic rescue by an mGluR5 modulator with selective normalization of neuronal transcriptomes. Alzheimer's disease symptoms are initiated by synapse loss in the setting of microglial reactivity, but the basis for immune mediator attack on synapses is not clear. The mGluR5 silent allosteric modulator (SAM), BMS-984923, prevents Alzheimer's triggered aberrant synaptic signaling while preserving physiological Glu activation. Here, we show that oral BMS-984923 effectively occupies brain mGluR5 sites visualized by [18F]FPEB PET at doses 250-fold below adverse effect doses in rodent and non-human primate. For aged transgenic and double knock-in mouse Alzheimer's models, SV2A PET imaging with [18F]SynVesT-1 reveals cortical and hippocampal synapse density decreases, which are fully recovered by SAM treatment. The disease-modifying benefit persists after drug washout. Tau accumulation in double knock-in mice is also reduced by SAM treatment. Single nuclei transcriptomics demonstrate that SAM treatment normalizes expression patterns to a much greater extent in neurons than glia. Production of the microglial mediator, C1q, is not altered by the mGluR5 compound, but Alzheimer gene-dependent C1q localization to synapses and synaptic engulfment are prevented. Thus, selective modulation of mGluR5 reverses neuronal gene expression changes to protect synapses from damage by microglial mediators. Overall design: An examination of silent allosteric modulator (SAM) of mGluR5, BMS-984923, binding effecacy at target receptors in rodent and non-human primate as well as it structural and functional effect in 2 rodent models of Alzheimeris disease.