The Role of the Classical Complement Cascade in Synapse Loss During Development and Glaucoma

Abstract

Glaucoma is one of the leading causes of vision loss worldwide, yet the signals that initiate the progressive degeneration of optic nerve axons and the selective loss of retinal ganglion neurons (RGCs) remain elusive. Reactive gliosis, release of inflammatory cytokines, and complement upregulation all occur in the early stages of glaucoma in several disease models. Recent work has implicated the classical complement cascade in the elimination of excess synaptic connections in the developing visual system and in early synapse loss associated with glaucoma, suggesting that mechanisms of developmental synapse elimination may be aberrantly re-activated in glaucoma. This review describes current evidence in support of this "synaptic" hypothesis and places complement in the context of other well-described mechanisms of neurodegeneration occurring in the glaucomatous eye.

The Complex Role of Neuroinflammation in Glaucoma

“…Components of the complement cascade play a significant role in immune surveillance and inflammatory processes, both peripherally and in the CNS (Janeway et al 2001). In addition to its involvement in pathogen targeting and elimination, the complement system is also involved in synapse elimination and clearance of potential mediators of damage or injury (Ricklin et al 2010;Rosen and Stevens 2010).…”

Intrinsic axonal degeneration pathways are critical for glaucomatous damage

“…Non-neuronal cells have also been shown to express potentially damaging molecules including complement components and endothelins (Chauhan 2008; Rosen & Stevens 2010). The complement cascade has important roles in innate immunity and in the pruning of neuronal synapses.…”

“…The complement cascade has important roles in innate immunity and in the pruning of neuronal synapses. Microglia synthesize and secrete key molecules of the complement cascade and may phagocyotse synapses (reviewed in (Perry et al 2010; Rosen & Stevens 2010)). Increased complement expression is reported in the optic nerve and retina for various glaucoma models and human glaucoma (reviewed in (Nickells et al submitted)).…”

Cerebrospinal fluid levels of complement proteins C3, C4 and CR1 in Alzheimer’s disease

“…In addition, the complement system has been shown to be involved in age-related macular degeneration (AMD) (Charbel Issa et al 2011) and glaucoma (Rosen and Stevens 2010), two neurodegenerative diseases with epidemiological and biochemical links to AD (Kaarniranta et al 2011;Kirby et al 2010).…”