Age-related Macular Degeneration

Abstract

10-20% of individuals over the age of 65 suffer from agerelated macular degeneration (AMD), the leading cause of severe visual impairment in humans living in developed countries. The pathogenesis of this complex disease is poorly understood, and no efficient therapy or prevention exists to date. A precondition for AMD appears to be the accumulation of the age pigment lipofuscin in lysosomes of retinal pigment epithelial (RPE) cells. In AMD, these cells seem to die by apoptosis with subsequent death of photoreceptor cells, and light may accelerate the disease process. Intracellular factors leading to cell death are not known. Here we show that the lipophilic cation N-retinyl-N-retinylidene ethanolamine (A2E), a lipofuscin component, induces apoptosis in RPE and other cells at concentrations found in human retina. Apoptosis is accompanied by the appearance of the proapoptotic proteins cytochrome c and apoptosis-inducing factor in the cytoplasm and the nucleus. Biochemical examinations show that A2E specifically targets cytochrome oxidase (COX). With both isolated mitochondria and purified COX, A2E inhibits oxygen consumption synergistically with light. Inhibition is reversed by the addition of cytochrome c or cardiolipin, a negatively charged phospholipid that facilitates the binding of cytochrome c to membranes. Succinate dehydrogenase activity is not altered by A2E. We suggest that A2E can act as a proapoptotic molecule via a mitochondria-related mechanism, possibly through site-specific targeting of this cation to COX. Loss of RPE cell viability through inhibition of mitochondrial function might constitute a pivotal step toward the progressive degeneration of the central retina. Age-related macular degeneration (AMD)1 affects 10 -20% of people at an age over 65 and constitutes one of the leading causes of severe visual impairment in the elderly in industrialized nations (1). Whereas the clinical and the histopathological pictures of AMD are well known (2, 3), molecular events initiating the disease remain elusive. Major obstacles in elucidating such events are the lack of suitable animal models and the complexity of the human disease. Recent studies indicate that genetic components (4 -8) and exogenous enhancing factors (9, 10) both contribute to the pathogenesis.In the course of photoreceptor renewal, rod outer segment tips are shed and phagocytosed by the underlying cells of the retinal pigment epithelium (RPE) (11-13). It is generally believed that the accumulation of the autofluorescent age pigment lipofuscin in RPE cell phagolysosomes constitutes a predicament for the development of the disease. Lipofuscin accumulation and the formation of drusen and other deposits in the region of Bruch's membrane, which separates the pigment epithelium from the underlying choroid are considered initial steps in the pathogenesis of AMD. Drusen formation may be the result of progressive death and/or exocytosis of RPE cells in the central retina (14, 15).Lipofuscin harbors two unusual retinoids, the lipophilic cations N-ret...

AMP kinase–mediated activation of the BH3-only protein Bim couples energy depletion to stress-induced apoptosis

“…The tissue was incubated with 0.25% trypsin-EDTA at 37°C for 15 min. After the incubation, the trypsinization was a rabbit polyclonal anti-AIF antibody (Suter et al, 2000) diluted 1:500 (gift from M. Jäättelä, Danish Cancer Society, Copenhagen, Denmark) or a rabbit polyclonal anti-phospho (Ser63) c-Jun antibody (Cell Signaling Technology) diluted 1:250. Primary antibodies were detected by incubation for 2 h at room temperature in a 1:500 dilution of either FITC-or rhodamineconjugated goat anti-rabbit secondary antibody (Jackson ImmunoResearch Laboratories, Inc.).…”

Isolation and characterization of a retinal pigment epithelial cell fluorophore: An all-trans -retinal dimer conjugate

“…Because of its amphiphilic properties, A2E can exert detergent-like effects on cell membranes (23)(24)(25)(26), perturb lysosomal function (27,28), and mediate blue-light damage (29)(30)(31). Blue-light irradiation of A2E leads to the photooxidation of A2E such that oxygens are added to carbon-carbon double bonds along the side arms of the molecule (32,33).…”

Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration

“…1B) (12,18), both of which are elevated in abcr Ϫ/Ϫ retinas (11,12). A2E sensitizes RPE cells to light-induced apoptosis (19)(20)(21) and has an inhibitory effect on phospholipid turnover in RPE phagolysosomes (22). Central blindness in Stargardt's patients results from photoreceptor degeneration caused by A2E-mediated toxicity to the RPE (11,21).…”