The good, the bad, and the opportunities of the complement system in neurodegenerative disease

Abstract

The complement cascade is a critical effector mechanism of the innate immune system that contributes to the rapid clearance of pathogens and dead or dying cells, as well as contributing to the extent and limit of the inflammatory immune response. In addition, some of the early components of this cascade have been clearly shown to play a beneficial role in synapse elimination during the development of the nervous system, although excessive complement-mediated synaptic pruning in the adult or injured brain may be detrimental in multiple neurogenerative disorders. While many of these later studies have been in mouse models, observations consistent with this notion have been reported in human postmortem examination of brain tissue. Increasing awareness of distinct roles of C1q, the initial recognition component of the classical complement pathway, that are independent of the rest of the complement cascade, as well as the relationship with other signaling pathways of inflammation (in the periphery as well as the central nervous system), highlights the need for a thorough understanding of these molecular entities and pathways to facilitate successful therapeutic design, including target identification, disease stage for treatment, and delivery in specific neurologic disorders. Here, we review the evidence for both beneficial and detrimental effects of complement components and activation products in multiple neurodegenerative disorders. Evidence for requisite co-factors for the diverse consequences are reviewed, as well as the recent studies that support the possibility of successful pharmacological approaches to suppress excessive and detrimental complement-mediated chronic inflammation, while preserving beneficial effects of complement components, to slow the progression of neurodegenerative disease.

Keywords: Alzheimer’s disease; Complement; Epilepsy; Microglia; Multiple sclerosis; Neurodegeneration; Neuroprotection; Stroke; Toll-like receptors; Traumatic brain injury.

Fig. 1

Activation pathways of the complement system. The complement system is activated by the classical, lectin, or alternative pathways. The classical pathway is activated when the C1 complex composed of C1q, C1r₂, and C1s₂, binds to apoptotic cells, neuronal blebs, fibrillar amyloid beta (fAβ), hyperphosphorylated tau, or antigen-antibody complexes via C1q. The lectin pathway is activated when mannan-binding lectin (MBL) in complex with MASP1/2 binds to microbial carbohydrates. Both pathways create the C3 convertase by cleaving C4 and C2 to form C4b2b. C3 is cleaved to form C3a, which promotes chemotaxis and activation of microglia via C3aR, and C3b can be cleaved to iC3b (by co-factors and factor I, not shown) to promote opsonization, or bind to C4b2b to form the C5 convertase (C4b2b3b). C5 is cleaved to form C5a, a potent inflammatory effector that acts through C5aR1 to promote chemotaxis and glial activation, and C5b, which binds to C6, C7, C8, and C9 to form the membrane attack complex (MAC) to permeate cell membrane and promote lysis. The alternative pathway can be activated when spontaneous hydrolysis of C3 to C3-H₂O enables factors B and D to generate the C3 convertase (C3(H₂O)Bb), which then cleaves other C3 molecules to C3b. The alternative pathway also forms an amplification loop for the other complement pathways, when factor B binds to C3b and is cleaved by factor D to form C3bBb which continues to cleave C3 to enhance the effect of activation. This also enables the C3bBb3b, alternative pathway C5 convertase, to cleave C5, releasing C5a and leading to the formation of the MAC

Fig. 2

Complement contributions to neuronal health, synaptic turnover, and self-perpetuating feed-forward inflammation and neuronal dysfunction in the CNS. (A) C1q synthesis is rapidly induced upon perturbation. C1q engagement with neurons after neuronal insult in the absence of the proteases C1r and C1s, promotes neuronal resilience. (B) As additional injury occurs, additional complement components C1r, C1s, C4, C2, and C3 are synthesized resulting in the formation of C1 complex, C1q, C1r₂, and C1s₂, and cleavage of C3 to C3b/iC3b, which promotes synaptic pruning by microglia via the CR3 receptor. (C) Further insults promote inflammation and complement activation. Once C3 is cleaved, if C5 is present, C5a is produced along with C3b and C3a. Inflammatory damage-associated microglia (DAM1) and damage-associated astrocytes (DAA) [141] are induced and promote neurotoxicity resulting in functional loss of neurons and eventual neuronal death. Neuronal death and/or overwhelmed clearance mechanisms further promote inflammation to continue the cycle of injury. DAAs and DAMs interact with DAMPS/PAMPS and complement C5a and C3a to perpetuate neurotoxicity