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.
Highlights
The complement system is foundational to the innate immune response in defending the body against invading pathogens by phagocytosis or by the activation of the adaptive immune system
It has been shown that complement components are upregulated during pre- and post-natal developmental stages of the central nervous system (CNS), while dramatically decreasing in the matured brain. This development-dependent dynamic change is essential for appropriate development, while imbalances in the complement cascades may result in vulnerability to developmental diseases, such as schizophrenia and autism [1,2,6,7,85]
A previous study observed that the increase of C1q in neurons and deposition of C3 in synapses are surrounded by phagocytotic microglia, which negatively correlates with the level of synaptic markers [17]
Summary
The complement system is foundational to the innate immune response in defending the body against invading pathogens by phagocytosis or by the activation of the adaptive immune system. Findings from studies presented in this review will show that complement components are produced by both neurons and glial cells. This local production of complement factors may be a developmental advantage as it enables a more rapid response than reliance on peripheral production and diffusion through the blood–brain barrier (BBB). The activation of the complement system in the CNS consists of over 30 complement factors under tight regulation [2]. 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 [3–5]. MAC: membrane attack complex; AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; MS: multiple sclerosis; PD: Parkinson’s disease; HD: Huntington’s disease; PNDs: perioperative neurocognitive disorders
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