Molecular pathology of age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the world. Although the etiology and pathogenesis of AMD remain largely unclear, a complex interaction of genetic and environmental factors is thought to exist. AMD pathology is characterized by degeneration involving the retinal photoreceptors, retinal pigment epithelium, and Bruch's membrane, as well as, in some cases, alterations in choroidal capillaries. Recent research on the genetic and molecular underpinnings of AMD brings to light several basic molecular pathways and pathophysiological processes that might mediate AMD risk, progression, and/or response to therapy. This review summarizes, in detail, the molecular pathological findings in both humans and animal models, including genetic variations in CFH, CX3CR1, and ARMS2/HtrA1, as well as the role of numerous molecules implicated in inflammation, apoptosis, cholesterol trafficking, angiogenesis, and oxidative stress.

Figures

Fig. 1

Hard and soft drusen. (A) Hard drusen, a small, discrete, punctate druse (arrow) with hyaline-like material located beneath the basal cell surface of the RPE and in Bruch’s membrane. (B) Soft drusen, large dome-shaped, hyaline granular deposits with poorly demarcated boundaries (arrow) beneath the RPE. Bruch’s membrane is thickened.

Fig. 2

Geographic atrophy in AMD. There is degeneration of RPE cells and most of the photoreceptors (asterisk).

Fig. 3

Neovascular AMD. There is a thin layer of fibrovascular membrane (CNV) between the RPE and Bruch’s membrane (arrows). Serous fluid (circles) due to leakage from neovascular membranes is seen in the outer plexiform layer of the retina.

Fig. 4

CX3CR1 in AMD eyes. (A) Different CX3CR1 SNP patterns are detected in AMD cases. Lane 1 demonstrates two bands (372, 216 bp), indicating homozygosity for the risk-conferring CX3CR1 T280M SNP. Lanes 2 and 3 reveal three bands (372, 297, 216 bp), representing heterozygous cases. Lane 4 demonstrates a wild-type (normal) case, which is indicated by two bands (297, 216 bp). (B) Low CX3CR1 expression (arrow) is observed in an AMD eye with CX3CR1 T280M.

Fig. 5

Decreased mitochondria in AMD retina. The number of mitochondria (M) is much lower in the inner segment of photoreceptors of the AMD eye (A) as compared with a normal age-control eye (B). Accumulation of lipofuscin is known to autofluoresce (in yellowish green color) in the RPE and drusen of the AMD eye (green: immunofluorescence staining with anti-human COV IV, a specific marker of mitochondria).

Fig. 6

HtrA1 expression in AMD eye. Positive immunoreactivity for HtrA1 is observed in the AMD lesion (circle) and residual RPE cells (arrow).