Age-Related Macular Degeneration: New Paradigms for Treatment and Management of AMD

Abstract

Age-related macular degeneration (AMD) is a well-characterized and extensively studied disease. It is currently considered the leading cause of visual disability among patients over 60 years. The hallmark of early AMD is the formation of drusen, pigmentary changes at the macula, and mild to moderate vision loss. There are two forms of AMD: the "dry" and the "wet" form that is less frequent but is responsible for 90% of acute blindness due to AMD. Risk factors have been associated with AMD progression, and they are taking relevance to understand how AMD develops: (1) advanced age and the exposition to environmental factors inducing high levels of oxidative stress damaging the macula and (2) this damage, which causes inflammation inducing a vicious cycle, altogether causing central vision loss. There is neither a cure nor treatment to prevent AMD. However, there are some treatments available for the wet form of AMD. This article will review some molecular and cellular mechanisms associated with the onset of AMD focusing on feasible treatments for each related factor in the development of this pathology such as vascular endothelial growth factor, oxidative stress, failure of the clearance of proteins and organelles, and glial cell dysfunction in AMD.

Figure 1

(a) Representative immunofluorescence image of the macula with geographic atrophy and loss of cones (red cells, mAb 7G6) over drusen. The RPE (orange) is thinned over drusen. Cell nuclei are blue (DAPI). 40x objective. (b) Nomarski image of the previous image. Note refractile drusen on Brunch's membrane (arrowhead). 40x objective. (c) Representative immunofluorescence image of the macula in a normal retina. Orange (RPE) and green (GFP) in astrocytes (anti-GFAP). (d) Representative immunofluorescence image of the macula with geographic atrophy. Orange (RPE) and green (GFP) in Müller cell scar (anti-GFAP). Photo credit: “The Human Retina in Health and Disease” Teaching Set by Ann H. Milam Ph.D., University of Pennsylvania.

Figure 2

A diagram illustrating the anatomical differences between RPE and BM on dry AMD (a) and wet AMD (b). Early AMD involves the accumulation of drusen and beta-amyloid peptides in the subretinal space. This might progress to dry AMD (a), which is characterized by inflammation and photoreceptor degeneration, caused in part by oxidative stress; resveratrol and alpha-lipoic acid prevent these effects. Autophagy induction by trehalose might help to eliminate intracellular components that abnormally accumulate intracellularly avoiding the following extracellular accumulation of toxic peptides, like beta-amyloid and lipids. Another strategy for the physiological recovery in AMD is the administration of induced pluripotent stem cells (iPSCs). Wet AMD (b) in which neovascularization from invading choroid vessels and the Bruch's membrane (BM) rupture cause photoreceptor damage. Besides, neovascularization of the retina ruptures the Bruch's membrane, which damages the macula and results in blurry or spotty vision. Anoxia and hypoxia-inducible factor 1 (HIF-1) induce the expression of VEGF-A, and as a possible treatment, thrombospondin-1 (TSP-1) protein might be used to block VEGF-A and metalloproteinases 2 and 9 (MMP-2 and MMP-9). Additionally, ranibizumab, aflibercept, bevacizumab, and bevasiranib could be used to block the angiogenic effects of VEGF on both cases.