New tricks for an ancient system: Physiological and pathological roles of complement in the CNS

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HighlightsComplement has critical functional roles in embryonic brain development.C1, C4, C2, C3 and CR3 are critical in synaptic refinement during brain maturation.Complement activation contributes to excessive synaptic pruning in CNS disorders.Determination of the molecular triggers of complement involvement will direct the pharmacologic development of interventions for currently intractable disorders of the CNS.While the mechanisms underlying the functions of the complement system in the central nervous system (CNS) and systemically, namely opsonization, chemotaxis, membrane lysis, and regulation of inflammation are the same, the plethora of functions that complement orchestrates in the central nervous system (CNS) is complex. Strictly controlled expression of complement effector molecules, regulators and receptors across the gamut of life stages (embryogenesis, development and maturation, aging and disease) dictate fascinating contributions for this ancient system. Furthermore, it is becoming apparent that complement functions differ widely across distinct brain regions. This review provides a comprehensive overview of the newly identified roles for complement in the brain, including its roles in CNS development and function, during aging and in the processes of neurodegeneration. The diversity and selectively of beneficial and detrimental activities of complement, while challenging, should lead to precision targeting of specific components to provide disease modifying treatments for devastating psychiatric and neurodegenerative disorders that are still without effective treatment.

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