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

Area of Science:

• Neuroscience
• Immunology
• Pharmacology

Background:

• Microglia-mediated synaptic loss is a key factor in Alzheimer's disease (AD) cognitive impairment.
• The precise mechanisms behind this immune attack on synapses are not fully understood.

Purpose of the Study:

• To investigate the therapeutic potential of BMS-984923, a metabotropic glutamate receptor 5 (mGluR5) silent allosteric modulator (SAM), in Alzheimer's disease models.
• To elucidate the mechanism by which BMS-984923 protects synapses from microglial-mediated damage.

Main Methods:

• Administration of BMS-984923 in aged mouse models of AD (APPswe/PS1ΔE9 and App/hMapt double knock-in).
• Positron emission tomography (PET) imaging using [18F]FPEB to assess brain mGluR5 occupancy and [18F]SynVesT-1 for synaptic vesicle glycoprotein 2A (SV2A) density.
• Histological analysis of synaptic density and phospho-TAU accumulation.
• Single-nuclei transcriptomics to analyze gene expression changes in neurons and glia.
• Assessment of complement component C1Q synaptic localization and synaptic engulfment.

Main Results:

• BMS-984923 treatment restored synaptic density, as confirmed by PET imaging and histology, with benefits persisting after drug washout.
• SAM treatment reduced phospho-TAU accumulation in double knock-in mice.
• Single-nuclei transcriptomics revealed that BMS-984923 normalized neuronal gene expression patterns more significantly than glial patterns.
• Treatment prevented the synaptic localization of C1Q and subsequent synaptic engulfment in AD mice.

Conclusions:

• Selective modulation of mGluR5 by BMS-984923 effectively reverses neuronal gene expression changes associated with AD.
• This mechanism protects synapses from damage induced by microglial mediators, offering a potential therapeutic strategy for Alzheimer's disease.