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

Abstract

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.

Keywords: C1q; C5a; Complement; Neurodegeneration; Neurodevelopment; Synapse pruning.

Figure 1. Microglia Prune Developing CNS Synapses in a complement-dependent manner

A Schematic of engulfment assay in which left and right eyes are injected with anterograde tracers, CTB-Alexa647 (blue) and CTB-Alexa488 (red), respectively B. Microglia (green) are visualized in the dLGN using a EGFP reporter mouse. C. Representative microglia (green) from the P5 dLGN surface rendered to visualize engulfed inputs (red and blue). [Grid line increments=5 μm] reveals presynaptic elements completely within microglia cytoplasm (green) (Schafer et al., Neuron 2012). Microglia engulfment of synapses is mediated, in part, by C3-CR3 phagocytic signaling as depicted on right.

Fig. 2. C1q and C5a: Homeostasis and neuroinflammation in AD

Proposed model of beneficial effects (green arrows) and detrimental effects (red arrows) of complement at different stages of AD progression.

Figure 3. C5aR1 Antagonist Suppresses AD-like Pathology in Mouse Models

PMX205 substantially reduces thioflavine plaques (A,B), microglial CD45 (C,D) and hyperphosphorylated tau (AT100, E,F) (45-70%) in Tg2576 (A-D) and 3×Tg (E,F). Scale bar is 100um (A,B) or 50um (C-F). From Fonseca et al. (2009) J. Immunology 183:1375–1383. (currently #68)