AMD and the alternative complement pathway: genetics and functional implications

Abstract

Age-related macular degeneration (AMD) is an ocular neurodegenerative disorder and is the leading cause of legal blindness in Western societies, with a prevalence of up to 8 % over the age of 60, which continues to increase with age. AMD is characterized by the progressive breakdown of the macula (the central region of the retina), resulting in the loss of central vision including visual acuity. While its molecular etiology remains unclear, advances in genetics and genomics have illuminated the genetic architecture of the disease and have generated attractive pathomechanistic hypotheses. Here, we review the genetic architecture of AMD, considering the contribution of both common and rare alleles to susceptibility, and we explore the possible mechanistic links between photoreceptor degeneration and the alternative complement pathway, a cascade that has emerged as the most potent genetic driver of this disorder.

Fig. 1

Illustration of the anatomical retinal pathology associated with the various AMD subtypes. Diagram of the outer layers of the human central retina in normal and in AMD. As the disease progresses, Bruch’s membrane (BM) increases in thickness. Early AMD is associated with small drusen and retinal pigmented epithelium (RPE) pigment abnormalities. As the disease progresses to the intermediate form, additional drusen are observed. In the two late forms of AMD (Dry and Wet), there is extensive drusen and photoreceptor cell death, with atrophy of the RPE and choroid in the Dry form and choroidal neovascularization (CNV), hemorrhaging, and RPE detachment in the Wet form. In all forms, the underlying circuitry including the horizontal and bipolar cells remains intact initially. This figure was prepared using Servier Medical Art (http://www.servier.com/Powerpoint-image-bank)

Fig. 2

The alternative complement pathway and the formation of the C3 convertase. In the AP, the generation of C3b can occur by either spontaneous hydrolysis of C3 (“tick-over” allowing for continuous low-level activation) or by plasma proteolytic cleavage all allowing for immediate C3b deposition. C3b forms the C3 convertase upon binding to FB and cleavage by FD resulting in an amplification loop producing additional C3b to stimulate a large immune response. C3b additionally binds to the C3 convertase leading to the formation of the C5 convertase initiating the terminal pathway and the establishment of the MAC. This figure was prepared using Servier Medical Art (http://www.servier.com/Powerpoint-image-bank)