Complement in neuroprotection and neurodegeneration

Abstract

Acute neurodegeneration is associated with high morbidity and mortality, and there are few effective treatments. Inflammation is central to the process of neuronal death, yet the roles of the complement cascade in this process have proven to be complex and hard to unravel. The complement cascade is involved in triggering cell death and recruiting cells of the immune system to sites of inflammation, including the brain. However, complement might also have important neuroprotective roles that are only now coming to light. Recent evidence suggests that targeted activation of complement might be a potential approach for treatment of stroke and other acute neurodegenerative diseases. Here, we review these novel neuroprotective roles of the complement cascade, focusing on signaling pathways that might provide new therapeutic targets in acute neuronal injury.

Figure 1. Apoptosis Signaling Pathways

The Intrinsic pathway is triggered by a disruption in the BAX:Bcl-2 protein ratio at the mitochondrion. Increase in this ratio allows for the homodimerization of BAX, and subsequent Cytochrome c efflux into the cytoplasm activates APAF-1. APAF-1 triggers Caspase 9 activation and the subsequent caspase cascade. The extrinsic pathway is triggered by ligand binding to the death receptors. Receptor activation leads to downstream recruitment of adapter proteins, such as FADD, resulting in the activation of Caspase 8 and the subsequent caspase cascade. Both pathways converge on Caspase 3, leading to apoptosis.

Figure 2. Complement Cascades

Three parallel complement cascades, the classical pathway, the alterative pathway, and the mannose-binding-lectin (MBL) pathway are activated by different immunological stimuli but ultimately converge on a common pathway that induces local inflammation, recruits phagocytes, and lyses cellular targets. A detailed description of these pathways is provided in Box 2.