Aberrant Complement System Activation in Neurological Disorders

Abstract

The complement system is an assembly of proteins that collectively participate in the functions of the healthy and diseased brain. The complement system plays an important role in the maintenance of uninjured (healthy) brain homeostasis, contributing to the clearance of invading pathogens and apoptotic cells, and limiting the inflammatory immune response. However, overactivation or underregulation of the entire complement cascade within the brain may lead to neuronal damage and disturbances in brain function. During the last decade, there has been a growing interest in the role that this cascading pathway plays in the neuropathology of a diverse array of brain disorders (e.g., acute neurotraumatic insult, chronic neurodegenerative diseases, and psychiatric disturbances) in which interruption of neuronal homeostasis triggers complement activation. Dysfunction of the complement promotes a disease-specific response that may have either beneficial or detrimental effects. Despite recent advances, the explicit link between complement component regulation and brain disorders remains unclear. Therefore, a comprehensible understanding of such relationships at different stages of diseases could provide new insight into potential therapeutic targets to ameliorate or slow progression of currently intractable disorders in the nervous system. Hence, the aim of this review is to provide a summary of the literature on the emerging role of the complement system in certain brain disorders.

The Role of Complement in Synaptic Pruning and Neurodegeneration

“…However, a different study of MS tissue from patients with a long disease duration (versus the early disease stages reported above) showed complement deposition across all types of white matter lesion. 95 Moreover, an increase in complement activation products has been directly associated with the severity of the pathology (reviewed in 18 ). In fact, in the EAE (Experimental autoimmune Encephalomyelitis) mouse model of MS, the use of a MAC inhibitor (C6 antisense oligonucleotides) reduced the expression of several inflammatory genes, further supporting the critical role of the MAC in tissue damage in MS. 96 However, although a C5-specific monoclonal antibody drug, Eculizumab, has been proven to prevent MAC formation and it has been approved for its use in Neuromyelitis Optica patients, there are still no studies showing its efficiency in MS patients.…”

Convergent Canonical Pathways in Autism Spectrum Disorder from Proteomic, Transcriptomic and DNA Methylation Data

“…Both cascades are involved in the inflammatory response by reactive microglia [ 153 , 154 ]. Coagulation proteins affect the morphology, proliferation, and function of astrocytes [ 153 ], while the complement system is implicated as a mechanism by which microglia regulate neurogenesis, neuronal migration and synaptic pruning [ 154 , 155 , 156 , 157 ]. Complement proteins play a role in microglial activation, which can influence neuroinflammatory signalling and neurodevelopment [ 158 ].…”

“…Animal models show that genetic knockdown of complement proteins impairs neuronal migration, while activation of the complement system rescues this deficit [ 155 ]. There is mounting evidence for complement system dysfunction in neurodevelopmental disorders [ 156 ], which has been proposed as one of the mechanisms behind the synaptic pruning deficits, increased dendritic spine density, cortical hyperconnectivity and resultant behavioural phenotypes in ASD [ 157 ]. Therefore, the immune response cascades enriched in ASD proteomic profiles function as a link between gliosis, neurogenesis, and synaptogenesis, highlighting a point of convergence between these different mechanisms in ASD pathology.…”

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

“…Under normal circumstances, the activation of the complement system in the CNS consists of over 30 complement factors under tight regulation [ 2 ]. However, when this well-tuned regulatory machinery malfunctions, aberrant complement factors can exacerbate neurological symptoms of brain conditions and accelerate the development of aging-related or neurodegenerative diseases [ 3 , 4 , 5 ]. Emerging evidence suggests that higher levels of complement factors are present in developing and degenerating brains and perform novel functions in neurodevelopment and contribute to the pathophysiology of neurodegenerative diseases [ 3 , 6 , 7 , 8 ].…”