Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q

Microglia-mediated synaptic loss contributes to the development of cognitive impairments in Alzheimer’s disease (AD). However, the basis for this immune-mediated attack on synapses remains to be elucidated. Treatment with the metabotropic glutamate receptor 5 (mGluR5) silent allosteric modulator (SAM), BMS-984923, prevents β-amyloid oligomer–induced aberrant synaptic signaling while preserving physiological glutamate response. Here, we show that oral BMS-984923 effectively occupies brain mGluR5 sites visualized by [18F]FPEB positron emission tomography (PET) at doses shown to be safe in rodents and nonhuman primates. In aged mouse models of AD (APPswe/PS1ΔE9 overexpressing transgenic and AppNL-G-F/hMapt double knock-in), SAM treatment fully restored synaptic density as measured by [18F]SynVesT-1 PET for SV2A and by histology, and the therapeutic benefit persisted after drug washout. Phospho-TAU accumulation in double knock-in mice was also reduced by SAM treatment. Single-nuclei transcriptomics demonstrated that SAM treatment in both models normalized expression patterns to a far greater extent in neurons than glia. Last, treatment prevented synaptic localization of the complement component C1Q and synaptic engulfment in AD mice. Thus, selective modulation of mGluR5 reversed neuronal gene expression changes to protect synapses from damage by microglial mediators in rodents. Description mGluR5 modulation rescues synaptic and transcriptomic alterations in experimental models of Alzheimer’s disease. A silent modulator for AD The loss of synapses observed in patients with Alzheimer’s disease (AD) contributes to the progressive cognitive impairments. Although microglia activity has been shown to participate in synaptic loss, the mechanisms mediating the process are not completely elucidated. Now, Spurrier et al. evaluated the role of metabotropic glutamate receptor 5 (mGluR5) on synaptic loss and showed that oral administration of an mGluR5 silent allosteric modulator (SAM) restored synaptic density and reduced phosphorylated TAU accumulation in mouse models of AD. Mechanistically, the treatment reversed gene expression changes induced in AD mice and prevented synaptic localization of the complement protein C1Q. The results suggest that SAMs targeting mGluR5 could be an effective approach for limiting AD-related synaptic loss.

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