Complement-dependent synapse loss and microgliosis in a mouse model of multiple sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory, neurodegenerative disease of the CNS characterized by both grey and white matter injury. Microglial activation and a reduction in synaptic density are key features of grey matter pathology that can be modeled with experimental autoimmune encephalomyelitis (EAE). Complement deposition combined with microglial engulfment has been shown during normal development and in disease as a mechanism for pruning synapses. We tested whether there is excess complement production in the EAE hippocampus and whether complement-dependent synapse loss is a source of degeneration in EAE using C1qa and C3 knockout mice. We found that C1q and C3 protein levels were elevated in EAE mice. Genetic loss of C1qa provided a small degree of protection from EAE-induced decreases in synaptic density. However, C1qa knockout EAE mice had similar levels of microglial activation and identical clinical scores as WT EAE mice. C3 knockout mice were largely protected from EAE-induced synapse loss and microglial activation, results that correlated with a reduction in the EAE clinical score. Thus, pathologic expression and activation of the early complement pathway drives a portion of the synapse elimination observed in the EAE grey matter.

Brain–Immune Interactions and Neuroinflammation After Traumatic Brain Injury

“…The knowledge on complement activation in AD and MS strongly suggests that the activation of the complement pathways in the long term after TBI could be an interesting mechanism in order to develop new therapeutic approaches for chronic TBI. It is possible that the pruning of synapses by complement-mediated microglia activation causes long-term neurological handicaps including cognitive impairment in various models of neurodegenerative diseases such as Alzheimer's disease, viral encephalitis, TBI, and MS and potentially contributes to schizophrenia (Stevens et al, 2007; Paolicelli et al, 2011; Ingram et al, 2014; Hong et al, 2016; Sekar et al, 2016; Vasek et al, 2016; Alawieh et al, 2018; Hammond et al, 2019). Therefore, inhibition of the long-term complement activation could improve TBI outcomes.…”

“…In EAE gray matter neurodegeneration, a significant synapse loss in the CA1 statum radiatum of the hippocampus reflecting cognitive impairment is caused by increased complement production and deposition of Cq1 and C3d that could make synapses vulnerable to phagocytosis by microglia. In particular, C3 mediates microglial activation and EAE motor impairments (Hammond et al, 2019). Altogether, there is convincing evidence that the complement activation is involved in MS disease development and the cerebral complement over-activation in inflammatory CNS lesions may be essential for the irreversible progression of MS.…”

Central nervous system diseases related to pathological microglial phagocytosis

“…The protein and mRNA levels of C1q and C3 increased in EAE mice. The loss of the C3 gene protected mice from EAE induced synaptic loss, reduced the activation of microglia, and enhanced the EAE clinical score 63 . Studies on postmortem human MS patients, primates, and two rodent demyelinating disease models, show that synaptic loss is not associated with local demyelination and neuronal degeneration.…”

The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors

“…Besides reduction in dendritic spine number, the postsynaptic scaffold protein Homer1 is also affected in the stratum radiatum after depletion of TBC1D24 in vivo. Although co-staining with a presynaptic marker has not been performed, given that majority of Homer1 or PSD-95 puncta are co-localized with each other and apposed to presynaptic terminals in the hippocampus in vivo [67,68,69], the number of postsynaptic puncta after single Homer1 or PSD-95 staining has been used to reflect the density of excitatory synapses [70,71,72,73]. Knockdown of TBC1D24 by shRNA reduces the density of Homer1 puncta in CA1 neurons, while both TBC1D24 knockdown and TBC1D24 F251L/+ heterozygous mutation lead to reduction of Homer1 puncta size and intensity in the hippocampus in vivo.…”