Alterations in Extracellular Matrix/Bruch's Membrane Can Cause the Activation of the Alternative Complement Pathway via Tick-Over.

Given the complex etiology of age-related macular degeneration (AMD), treatments are developed to target intermediate/late stages of the disease. Unfortunately, the design of therapies for early stages of the disease is limited by our understanding of the mechanisms involved in the formation of basal deposits and drusen, the first clinical signs of AMD. During the last decade, the identification of common and rare alleles in complement genes as risk AMD variants in addition to the presence of active complement components in basal deposits and drusen has provided compelling evidence that the complement system plays a key role in the pathobiology of AMD. However, the mechanisms for complement activation in AMD are unknown. Here we propose that the activation of the complement system is a consequence of alterations in the aged extracellular matrix (ECM) of the retinal pigment epithelium (RPE)/Bruch's membrane (BrM), which favors the anchoring of complement C3b generated by convertase-independent cleavage of C3 via tick-over and produces a chronic activation of the alternative complement pathway.