To determine complement system role, mechanism and pathway in neurodegenerative disease, such as Alzheimer's disease (AD).

Brains of Alzheimer's disease (AD) are characterized by neuroinflammation and synaptic loss.

Microglia and complement appear to be involved in the synaptic and cognitive deficits seen in AD, though the mechanisms remain elusive.

Two types of rodent models of AD, rats injected with amyloid fibrils into hippocampal CA1 and transgenic APP/PS1 mice, were used in this study. Immunostaining was applied to study the microglia phagocytosis of glutamatergic synapse, which was analyzed by confocal 3-D image. Immunoblotting was used to study the expression of C1q and other proteins. Whole-cell recording and Morris water maze were used to evaluate the synaptic and cognitive function in the rodent models.

Increasing complement C1q-mediated microglial phagocytosis of the hippocampal glutamatergic synapses that resulted in synaptic and cognitive deficits in models of AD. Second, increasing activity of the metabotropic glutamate receptor 1 (mGluR1) in the hippocampal CA1 area. Suppression of mGluR1- protein phosphatase 2 (PP2A) signaling inhibited the dephosphorylation of FMRP and repressed the local translation of synaptic C1q mRNA, which consequently alleviated the microglial phagocytosis of synapses in the hippocampal CA1 and restored the synaptic and cognitive function in the rodent models. Artificial activation of mGluR1 signaling by DHPG promoted dephosphorylation of fragile X mental retardation protein (FMRP) and facilitated the local translation machinery of synaptic C1q mRNA, mimicking the C1q-mediated microglial phagocytosis of hippocampal glutamatergic synapses and synaptic and cognitive deficiency in the rat model.

Activation of mGluR1-PP2A signaling by amyloid fibrils induced the dephosphorylation of FMRP, which facilitated the local translation of C1q mRNA in both rodent models.

This led to C1q-mediated microglial phagocytosis of hippocampal glutamatergic synapses, which contributed to the development of synaptic and cognitive deficiency in AD.