Activation of mGluR1 Mediates C1q-Dependent Microglial Phagocytosis of Glutamatergic Synapses in Alzheimer’s Rodent Models

  • Bihua Bie
  • Jiang Wu
  • Joseph F. Foss
  • Mohamed NaguibEmail author


Microglia and complements appear to be involved in the synaptic and cognitive deficits in Alzheimer’s disease (AD), though the mechanisms remain elusive. In this study, utilizing two types of rodent model of AD, we reported increased complement C1q-mediated microglial phagocytosis of hippocampal glutamatergic synapses, which led to synaptic and cognitive deficits. We also found increased activity of the metabotropic glutamate receptor 1 (mGluR1) in hippocampal CA1 in the modeled rodents. Artificial activation of mGluR1 signaling promoted dephosphorylation of fragile X mental retardation protein (FMRP) and facilitated the local translation machinery of synaptic C1q mRNA, thus mimicking the C1q-mediated microglial phagocytosis of hippocampal glutamatergic synapses and synaptic and cognitive deficiency in the modeled rodents. However, suppression of mGluR1 signaling inhibited the dephosphorylation of FMRP and repressed the local translation of synaptic C1q mRNA, which consequently alleviated microglial phagocytosis of synapses and restored the synaptic and cognitive function in the rodent models. These findings illustrate a novel molecular mechanism underlying C1q-mediated microglial phagocytosis of hippocampal glutamatergic synapses in AD.


Alzheimer’s disease Complement C1q Metabotropic glutamate receptor Fragile X mental retardation protein Microglial phagocytosis Synaptic loss 



The authors thank John Peterson, Ph.D., Imaging Core, Cleveland Clinic for his expertise and help provided for imaging analysis.

Funding Information

Dr. Naguib is supported by the National Institute of Aging of the National Institutes of Health under Award Number R56AG051594. This work utilized the Leica SP8 confocal microscope that was purchased with funding from the National Institutes of Health SIG grant1S10OD019972-01.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2019_1467_MOESM4_ESM.docx (283 kb)
ESM 1 (DOCX 283 kb)


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Authors and Affiliations

  1. 1.Anesthesiology InstituteCleveland ClinicClevelandUSA
  2. 2.Cleveland Clinic Lerner College of MedicineCase Western Reserve UniversityClevelandUSA

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