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.

Microglial Pruning: Relevance for Synaptic Dysfunction in Multiple Sclerosis and Related Experimental Models

“…Regardless of the initial trigger, the reactivation of aberrant pruning can cause synaptic loss as a consequence of excessive complement deposition. Studies concerning this aspect of neurodegeneration have been performed in mouse models, but observations consistent with this notion have also been reported in post-mortem examinations of human brain samples [ 49 ]. In this instance, AD represents a form of neurodegeneration in which aberrant pruning and exacerbated neuroinflammation involving activated microglia are strongly implicated in the genetics and neuropathology of the disease.…”

“…The role of the complement in MS pathology is well established, as reviewed by Ingram et al, and it has also been proposed as a biomarker of the disease [ 124 ]. Alongside its known role in the opsonization of myelin fragments [ 124 , 125 , 126 ] and in the progression of the disease [ 49 , 127 , 128 ], much evidence also suggests its contribution to MS- and EAE-related synaptopathy. In MS, elevated levels of C3 in CSF correlate both with those of the light subunit of the neurofilament protein, marker of ongoing neuronal damage, and with levels of clinical disability [ 129 ].…”

The Sez6 Family Inhibits Complement by Facilitating Factor I Cleavage of C3b and Accelerating the Decay of C3 Convertases

“…The complement system has three initiating pathways (classical, alternative, and lectin) that all create C3 convertases to cleave C3 [reviewed in ( 35 , 36 )]. The classical/lectin pathway C3 convertase is composed of C4b2b [formerly called C4b2a ( 37 )].…”

“…A common feature of complement regulators that inhibit C3 convertases is the presence of three or more tandem CCP domains ( 29 , 38 ). The most well-known CCP containing complement regulators are DAF/CD55, MCP/CD46, and CR1 (or Crry in rodents) which are membrane-associated and Factor H (FH) and C4BP, which are soluble circulating factors ( 35 , 36 ). Complement regulators can deactivate C3 convertases by dissociating the protease subunits (Bb/2b) from the non-catalytic subunits (C3b/C4b), which has been defined as “decay accelerating” activity.…”

Alternative Targets to Fight Alzheimer’s Disease: Focus on Astrocytes

“…Complement factors have been shown to be elevated during AD progression, likely as a general reaction to abnormal protein deposition and other cerebral injuries that occur in the AD brain [ 108 , 109 , 110 ]. This is not surprising, since the complement cascade is a fundamental effector of the innate immune system that favors the rapid clearance of pathogens, apoptotic cells, and their debris, as well as the extent and termination of the inflammatory immune response [ 111 ]. Some components of the complement cascade play a key role in synapse pruning.…”