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.
Highlights
The complement system is composed of a large family of circulating and membraneassociated proteins that act synergistically in a sequential cascade-like manner to execute and regulate its function
One illuminating experiment conducted by Mocco et al [20] showed that the deletion of C5 did not offer protection after transient focal ischemia, but another group demonstrated a reduction in infarct size and attenuated neurological deficits in a model of permanent stroke associated with long-term activation of C5 [54]
Several mechanisms may contribute to secondary pathology caused by Spinal cord injury (SCI), including axonal injury, demyelination, excitotoxicity, oxidative damage, and inflammation frequently associated with disruption of the blood-spinal cord barrier and recruitment of immune cells [101]
Summary
The complement system is composed of a large family of circulating and membraneassociated proteins that act synergistically in a sequential cascade-like manner to execute and regulate its function. The alternative pathway is triggered by hydrolysis of C3 to C3-H2 O; factors B and D generate the C3 convertase—C3(H2 O)Bb, which cleaves other C3 molecules to C3a and C3b This in turn forms C3bBb complex which continues cleavage of the C3 and enables formation of the C5 convertase—C3bBb3b, which cleaves C5 and leads to the formation of the MAC. Alterations in complement-mediated synaptic remodeling are hypothesized to contribute to synapse dysfunction and decline in cognitive functions in several neurodegenerative and psychiatric disorders. As another option, complement activation fragments can induce local stimulation of microglia/astrocytes that together with other proinflammatory cascades accelerate pathogenesis and neuronal damage. The aim of this review is to provide a brief summary of the current knowledge about the functional role of complement regulation in selected neuropathologies, including ischemia, traumatic brain injury, spinal cord injury, neurodevelopmental impairments (schizophrenia and autism spectrum disorder), neurodegenerative diseases, and chronic disorders such as Parkinson disease (PD), Huntington disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and epilepsy
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