The complement system in neurodegenerative diseases

Abstract

Complement is an important component of innate immune defence against pathogens and crucial for efficient immune complex disposal. These core protective activities are dependent in large part on properly regulated complement-mediated inflammation. Dysregulated complement activation, often driven by persistence of activating triggers, is a cause of pathological inflammation in numerous diseases, including neurological diseases. Increasingly, this has become apparent not only in well-recognized neuroinflammatory diseases like multiple sclerosis but also in neurodegenerative and neuropsychiatric diseases where inflammation was previously either ignored or dismissed as a secondary event. There is now a large and rapidly growing body of evidence implicating complement in neurological diseases that cannot be comprehensively addressed in a brief review. Here, we will focus on neurodegenerative diseases, including not only the 'classical' neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, but also two other neurological diseases where neurodegeneration is a neglected feature and complement is implicated, namely, schizophrenia, a neurodevelopmental disorder with many mechanistic features of neurodegeneration, and multiple sclerosis, a demyelinating disorder where neurodegeneration is a major cause of progressive decline. We will discuss the evidence implicating complement as a driver of pathology in these diverse diseases and address briefly the potential and pitfalls of anti-complement drug therapy for neurodegenerative diseases.

Keywords: complement; dementia; inflammation.

Figure 1. The complement cascade

The complement system is activated via the classical, lectin, or alternative pathways. The classical pathway is initiated by C1 binding to antigen-antibody complexes or in brain directly to amyloid, tau or α-Syn aggregates. C1s in the C1 complex cleaves C4 and C2 to form the C3 convertase C4b2a. The lectin pathway is activated by MBL or other lectins binding surface carbohydrates; attached MASPs are activated to cleave C4 and C2 to generate C4b2a. The C3 convertase cleaves C3 to C3b and C3a, the former is further processed by Factor I (FI) to form the opsonin iC3b, a ligand for phagocyte complement receptors CR3 and CR4 to initiate phagocytosis. C3b also feeds back to generate more C3 convertase via the amplification loop; factor B (FB) binds C3b and is then cleaved by factor D (FD) to create the alternative pathway C3 convertase C3bBb. Binding of a further C3b to either C3 convertase creates a C5 convertase which cleaves C5 to initiate the terminal pathway culminating in formation of the membrane attack complex (MAC). The small fragments generated from the C3 and C5 convertases, C3a and C5a, are anaphylatoxins and signal via their receptors, C3aR and C5aR, to recruit immune cells. Numerous cell surface and fluid-phase proteins regulate complement activation and terminal pathway, including C1-inhibitor (C1INH), which inhibits C1s and MASPs, decay accelerating factor (DAF), complement receptor 1 (CR1) and Factor H (FH) which regulate the C3 convertases clusterin, vitronectin and CD59 which control MAC assembly. Complement drugs in clinical/pre-clinical trials are shown in red. GWAS hits in specific diseases are shown in blue. Figure created with BioRender (BioRender.com).

Figure 2. Complement in healthy and neurodegenerative brain

In the healthy brain, as in other organs, complement plays a crucial role in defending against infections and maintaining tissue homeostasis. These homeostatic roles include the core complement functions of immune surveillance to detect and eliminate pathogens and to remove dead cells and debris (in collaboration with microglia), and the brain-specific role of synaptic pruning. In the NDD brain, complement is dysregulated, generating an excess of pro-inflammatory products that trigger hyper-activation of microglia (and other glia), production of diverse proinflammatory mediators and increased phagocytosis. Terminal pathway activation and MAC formation directly damages neurones and synapses, precipitating neurodegeneration. Figure created with BioRender (BioRender.com).