Understanding age-related macular degeneration (AMD): Relationships between the photoreceptor/retinal pigment epithelium/Bruch’s membrane/choriocapillaris complex

Abstract

There is a mutualistic symbiotic relationship between the components of the photoreceptor/retinal pigment epithelium (RPE)/Bruch’s membrane (BrMb)/choriocapillaris (CC) complex that is lost in AMD. Which component in the photoreceptor/RPE/BrMb/CC complex is affected first appears to depend on the type of AMD. In atrophic AMD (~85–90% of cases), it appears that large confluent drusen formation and hyperpigmentation (presumably dysfunction in RPE) are the initial insult and the resorption of these drusen and loss of RPE (hypopigmentation) can be predictive for progression of geographic atrophy (GA). The death and dysfunction of photoreceptors and CC appear to be secondary events to loss in RPE. In neovascular AMD (~10–15% of cases), the loss of choroidal vasculature may be the initial insult to the complex. Loss of CC with an intact RPE monolayer in wet AMD has been observed. This may be due to reduction in blood supply because of large vessel stenosis. Furthermore, the environment of the CC, basement membrane and intercapillary septa, is a proinflammatory milieu with accumulation of complement components as well as proinflammatory molecules like CRP during AMD. In this toxic milieu, CC die or become dysfunction making adjacent RPE hypoxic. These hypoxic cells then produce angiogenic substances like VEGF that stimulate growth of new vessels from CC, resulting in choroidal neovascularization (CNV). The loss of CC might also be a stimulus for drusen formation since the disposal system for retinal debris and exocytosed material from RPE would be limited. Ultimately, the photoreceptors die of lack of nutrients, leakage of serum components from the neovascularization, and scar formation. Therefore, the mutualistic symbiotic relationship within the photoreceptor/RPE/BrMb/CC complex is lost in both forms of AMD. Loss of this functionally integrated relationship results in death and dysfunction of all of the components in the complex.

Risk of geographic atrophy in age-related macular degeneration patients treated with intravitreal anti-VEGF agents

“…This is consistent with the finding that photoreceptor and RPE degenerate in a horse-shoe-shaped pattern surrounding the fovea as mentioned above, 15 regardless of the timing of events (does RPE atrophy occur first or does CC degeneration precede RPE atrophy?) and of the form of AMD (dry AMD or combined CNV and GA).…”

“…'RPE atrophy vs choroidal atrophy' in AMD According to Bhutto and Lutty 15 there is a 'mutualistic symbiotic relationship' between the components of the photoreceptor/RPE/Bruch's membrane/CC complex and subsequently between degenerating RPE and CC. Lutty's lab team had previously shown that at least in advanced dry AMD (GA), RPE atrophy occurs first, followed by CC degeneration, whereas CC degeneration precedes RPE atrophy in wet AMD.…”

Quantitative optical coherence tomography angiography of vascular abnormalities in the living human eye

“…In advanced nonneovascular AMD, geographic atrophy (GA) is associated with loss of photoreceptors, RPE, and the choriocapillaris. Whether the RPE or choriocapillaris alterations are the primary event in pathogenesis has been a matter of debate (26). Histologic studies have described choriocapillaris dysfunction in the intermediate stage of AMD, before development of GA or choroidal neovascularization (27,28).…”

The marine n-3 PUFA DHA evokes cytoprotection against oxidative stress and protein misfolding by inducing autophagy and NFE2L2 in human retinal pigment epithelial cells

“…91,92 The pathogenesis of AMD is strongly associated with oxidative stress. 10,18,20,93,94 Currently, there is no established prevention or therapy for early AMD. The Age-Related Eye Disease Study (AREDS) is among the largest and most robust randomized clinical trials designed to investigate the role of daily oral supplementation of antioxidant vitamins and minerals.…”