2015
DOI: 10.1016/j.preteyeres.2014.11.005
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Complement activation and choriocapillaris loss in early AMD: Implications for pathophysiology and therapy

Abstract: Age-related macular degeneration (AMD) is a common and devastating disease that can result in severe visual dysfunction. Over the last decade, great progress has been made in identifying genetic variants that contribute to AMD, many of which lie in genes involved in the complement cascade. In this review we discuss the significance of complement activation in AMD, particularly with respect to the formation of the membrane attack complex in the aging choriocapillaris. We review the clinical, histological and bi… Show more

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Cited by 193 publications
(173 citation statements)
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“…[11][12][13][14][15] Cellular changes in advanced AMD include atrophy of the RPE, choriocapillaris and outer retina in nonexudative AMD, and the development of choroidal neovascularization in exudative AMD. [16][17][18] At the current time, any connection between ultrastructural changes observed in BM with age (mentioned above) and cellular changes that develop in AMD is not known. However, it is known that the structural changes that are due to aging within BM precede cellular changes in the RPE by one or two decades, well before there are signs of early AMD on clinical examination and imaging.…”
Section: Introductionmentioning
confidence: 99%
“…[11][12][13][14][15] Cellular changes in advanced AMD include atrophy of the RPE, choriocapillaris and outer retina in nonexudative AMD, and the development of choroidal neovascularization in exudative AMD. [16][17][18] At the current time, any connection between ultrastructural changes observed in BM with age (mentioned above) and cellular changes that develop in AMD is not known. However, it is known that the structural changes that are due to aging within BM precede cellular changes in the RPE by one or two decades, well before there are signs of early AMD on clinical examination and imaging.…”
Section: Introductionmentioning
confidence: 99%
“…Immunostaining of human donor tissue shows that CD59 is predominantly found on the apical surface (16). Decreased CD59 expression (16) and increased MAC deposition in sub-RPE drusen and at the RPE-choroid interface (13,17) have been detected in AMD patient tissues, pointing to a breakdown in mechanisms that prevent MAC assembly. Activated complement components have also been detected in retinal tissue from the Abca4 −/− mouse model of Stargardt macular dystrophy, characterized by lipofuscin accumulation and accelerated formation of vitamin A dimers, such as A2E, in the RPE (7,8).…”
mentioning
confidence: 99%
“…Cardinal features include accumulation of lipids and proteins within drusen and Bruch's membrane (6), RPE dysfunction/death, complementmediated attack and vaso-obliteration of the choriocapillaris (7), and photoreceptor atrophy ( Figure 1B). However, the precise etiology of AMD is unclear (7,8), and according to some experts it may be a spectrum of closely related diseases (9). Both genetic and environmental influences confer risk, but it is unclear which outer retinal components are affected first by the insult(s), and the order in which they are affected may differ between cases (8).…”
Section: Amdmentioning
confidence: 99%
“…First, the PI3/Akt/mTOR pathway has been shown to regulate RPE metabolism (21), and stimulation of the insulin/mTOR pathway in murine retinas significantly retards photoreceptor atrophy (22). Second, variants in complement cascade genes including CFH, CFI, CFB, and C3 are associated with AMD, and complement-mediated attacks on the choriocapillaris might be a primary event in AMD pathogenesis (7). Third, ECM receptor interactions are critical for choriocapillaris, Bruch's membrane, and RPE crosstalk (23).…”
Section: Nicotinamide Suppresses Signaling Cascades In Rpe That Mightmentioning
confidence: 99%