Age-Related Macular Degeneration: A Complementopathy?

Abstract

Age-related macular degeneration (AMD) is a progressive eye disease affecting many elderly individuals. It has a multifactorial pathogenesis and is associated with numerous environmental (e.g. smoking, light and nutrition) and genetic risk factors. A breakthrough in the mechanisms causing AMD is emerging; the involvement of the alternative pathway of the complement system appears to play a pivotal role. This has led to the statement that AMD is a disease caused by a hyperactive complement system, allowing the term ‘complementopathy' to define it more precisely. Abundant evidence includes: the identification of drusen components as activators of complement, immunohistochemical data showing the presence of many species of the complement system in the retinal pigment epithelium-Bruch's membrane-choroidocapillary region of AMD eyes, a strong association of AMD with certain genetic complement protein variants, raised complement levels in blood from AMD patients and the preliminary successful treatments of geographic atrophy with complement factor D (FD) inhibitors. FD is the rate-limiting enzyme of the alternative complement pathway, and is produced by adipose tissue. Recent findings suggest that nutrition may play a role in controlling the level of FD in the circulation. Addressing modifiable risk factors such as smoking and nutrition may thus offer opportunities for the prevention of AMD.

Efficacy of a Fatty Acids Dietary Supplement in a Polyethylene Glycol-Induced Mouse Model of Retinal Degeneration

“…Therefore, PEG-400 may potentially impair the control that proteases exert on the complement system [ 30 ], thus contributing to the formation of the terminal complement. Hence, activation of the complement receptors on the RPE by PEG-400-upregulated C3 and C5 participates in the pathological lesions observed in the outer retina and Bruch’s membrane [ 31 ]. Upregulation of the complement system found here is in line with previous results in models of dry AMD [ 13 , 32 ], and is in agreement with the finding that mice lacking of CD46, a membrane cofactor protein that plays a key role in the complement alternative pathway [ 33 ], demonstrate spontaneous age-related degenerative changes in the retina, RPE, and choroid that are consistent with the cardinal features of human AMD [ 34 ].…”

Recent developments in age-related macular degeneration: a review

“…It is believed that the pathogenesis of AMD is the result of a complex multifactorial interaction between metabolic, functional, genetic, and environmental factors. 5 With aging, intracellular residual bodies containing lipofuscin accumulate in RPE cells. 6 RPE cells express such materials that would normally be eliminated by the choriocapillaris; however, as RPE dysfunction progresses, it results in alterations in the permeability of Bruch’s membrane, which leads to an accumulation of extruded material (drusen) between the two layers.…”

Advances in Age-related Macular Degeneration Understanding and Therapy

“…Greater increases in complement protein plasma levels have been associated with advanced stages of AMD, leading to the hypothesis that complement activation may be correlated with disease progression as well. 45 , 46 There is weak evidence that genetic polymorphisms in CHF associated with AMD may lead to over-activity of complement. Scholl et al found that median plasma concentrations of CHF were not increased in patients with AMD, 47 whereas complement factor D (CFD) levels did, indicating that CFD may be a more promising target for AMD therapy than CHF.…”