The Complement System in the Central Nervous System: From Neurodevelopment to Neurodegeneration

Abstract

The functions of the complement system to both innate and adaptive immunity through opsonization, cell lysis, and inflammatory activities are well known. In contrast, the role of complement in the central nervous system (CNS) which extends beyond immunity, is only beginning to be recognized as important to neurodevelopment and neurodegeneration. In addition to protecting the brain against invasive pathogens, appropriate activation of the complement system is pivotal to the maintenance of normal brain function. Moreover, overactivation or dysregulation may cause synaptic dysfunction and promote excessive pro-inflammatory responses. Recent studies have provided insights into the various responses of complement components in different neurological diseases and the regulatory mechanisms involved in their pathophysiology, as well as a glimpse into targeting complement factors as a potential therapeutic modality. However, there remain significant knowledge gaps in the relationship between the complement system and different brain disorders. This review summarizes recent key findings regarding the role of different components of the complement system in health and pathology of the CNS and discusses the therapeutic potential of anti-complement strategies for the treatment of neurodegenerative conditions.

Erythrocytes as Messengers for Information and Energy Exchange between Cells

“…It should be noted that brain expression of CR1 is controversial, and therefore the erythrocyte-based explanation for CR1 involvement in Alzheimer's disease is preferred [45]. Complement has been shown to be active in normal brain function, for instance by performing synaptic pruning during development [49,50]. The other complement components or complement factors that have been implicated in Alzheimer's disease may therefore be active in the brain.…”

The cytokine receptor Fn14 is a molecular brake on neuronal activity that mediates circadian functionin vivo

“…The competitive removal of a subset of immature synapses by microglia facilitates the strengthening and maintenance of a separate cohort of synapses, thereby driving circuit maturation. Furthermore, neurons themselves express numerous cytokines, cytokine receptors, and other immune-related signaling proteins, including Major Histocompatibility Complex (MHC) class I molecules and components of the classical complement cascade, which localize to developing synapses to mediate their elimination, remodeling, or strengthening via both microglia-dependent and microglia-independent mechanisms [8][9][10] . Thus, cytokines and their receptors are essential for brain development.…”

Complement C4-deficient mice have a high mortality rate during PTZ-induced epileptic seizures, which correlates with cognitive problems and the deficiency in the expression of Egr1 and other immediate early genes

“…The complement system consists of more than 30 proteins forming an enzymatic activating cascade that is initiated by various “danger signals” such as pathogens, cellular debris, apoptotic bodies, and blood coagulation processes ( Foley and Conway, 2016 ; Reis et al, 2019 ). Specifically, complement may be activated via the classical, lectin, and alternative pathways, or an extrinsic blood coagulation cascade ( Foley and Conway, 2016 ; Chen et al, 2022 ). The classical pathway is initiated by antigen–antibody complexes that bind C1q, leading to the proteolytic cleavage of C2 into C2a and C2b fragments, and then cleavage of C4 into C4a and C4b fragments.…”

“…The liver is the dominant source of most complement proteins in the plasma or serum, except for C1q, which is mainly synthesized by immune cells. In the central nervous system (CNS), several complement components, including C1q, C4, and C3 are synthesized by astrocytes, oligodendrocytes, neurons, and microglia ( Cho, 2019 ; Schartz and Tenner, 2020 ; Peoples and Strang, 2021 ; Chen et al, 2022 ). In the normal CNS, microglia produce C1q, which then recruits C3 to axons via activation of C4 in the classical pathway and thus marks unfunctional synapses for elimination by microglia via microglial complement receptor 3 (CR3) that specifically binds to C3b ( Stevens et al, 2007 ; Paolicelli et al, 2011 ; Cho, 2019 ; Gomez-Arboledas et al, 2021 ).…”

“…In the normal CNS, microglia produce C1q, which then recruits C3 to axons via activation of C4 in the classical pathway and thus marks unfunctional synapses for elimination by microglia via microglial complement receptor 3 (CR3) that specifically binds to C3b ( Stevens et al, 2007 ; Paolicelli et al, 2011 ; Cho, 2019 ; Gomez-Arboledas et al, 2021 ). It was recently demonstrated that the complement system is involved in the pathogenesis of many types of neurologic diseases including traumatic brain injury, Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and multiple sclerosis ( Schartz and Tenner, 2020 ; Gomez-Arboledas et al, 2021 ; Chen et al, 2022 ). Genome-wide association studies demonstrated a strong association between human C4 gene polymorphisms and schizophrenia (SZ) ( Sekar et al, 2016 ).…”