Molecular pathology of age-related macular degeneration
Introduction
Age-related macular degeneration (AMD) was first described in the medical literature in 1875 as “symmetrical central choroidoretinal disease occurring in senile persons” (Hutchison and Tay, 1875). According to the most recent report on the causes of visual impairment by the World Health Organization in 2002, AMD is among the most common causes of blindness, particularly irreversible blindness, in the world. Among the elderly, AMD is regarded as the leading cause of blindness in the world (Gehrs et al., 2006). Currently, in the United States alone, 1.75 million people are affected by AMD and 7 million people are at risk of developing AMD (Friedman et al., 2004). Considering the significant medical, personal, social, and economic costs of AMD, the need for novel therapeutic and preventative strategies for AMD is pressing. Innovation in AMD pharmacotherapy, in turn, depends largely upon a thorough understanding of the molecular mechanisms underlying AMD pathogenesis.
AMD is a highly complex disease with demographic, environmental, and genetic risk factors. Among demographic and environmental factors associated with AMD, such as age, gender, race, diet, smoking, education, cardiovascular disease, studies have shown that the most established factors are advanced age, cigarette smoking, diet, and race (Coleman et al., in press, Jager et al., 2008). The age-associated increase in AMD risk might be mediated by gradual, cumulative damage to the retina from daily oxidative stress. Loss of normal physiological function in the aging retinal pigment epithelial (RPE) cells, a specialized neural cell of neuroectoderm origin that provides metabolic support to photoreceptor cells, may also contribute to the formation of drusen deposits classically seen in AMD retina. Alternatively, age-related mitochondrial DNA damage might also play a role in pathogenesis. Further studies on the impact of aging on the structure and function of the retina are certainly necessary to parse out the key pathological changes that lead to AMD.
The relationship between smoking and AMD has been investigated in numerous cross-sectional studies, cohort studies, and case–control studies (Klein, 2007). The majority of studies have found a statistically significant association between smoking and development of AMD. Possible mechanisms by which smoking mediates increased AMD risk include impairment in the generation of antioxidants (e.g. plasma vitamin C and carotenoids) induction of hypoxia, generation of reactive oxygen species, and alteration of choroidal blood flow. Smoking also has an effect on the immune system (Tsoumakidou et al., 2008). Based on studies (discussed below) demonstrating an immunological component for AMD, it is possible that part of the risk conferred by smoking funnels through inflammatory pathways. This remains to be demonstrated experimentally.
Both fat intake and obesity have been linked to increased risk of AMD (Mares-Perlman et al., 1995, Seddon et al., 2003), and analyses have revealed protective effects from antioxidants, nuts, fish, and omega-3 polysaccharide unsaturated fatty acids (AREDS (Age-Related Eye Disease Study Research Group), 2001, Cho et al., 2001, Seddon et al., 1994, Seddon et al., 2001, Smith et al., 2000). Several convincing studies of the dietary effect on AMD are from randomized controlled clinical trials, e.g., Age-Related Eye Disease Study (AREDS), VEGF (Vascular endothelial growth factor) Inhibition Study in Ocular Neovascularization, Clinical Trial and Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) (AREDS (Age-Related Eye Disease Study Research Group), 2001, Bressler et al., 2003, Gragoudas et al., 2004, Rosenfeld et al., 2006). The AREDS demonstrated the efficacy of zinc-antioxidant supplements for preventing or delaying progression of early AMD to late AMD in patients who are at high risk (Bressler et al., 2003). A recent population-based cohort study in Australia (Tan et al., 2008) demonstrated that high dietary lutein and zeaxanthin intake reduced the risk of long-term incident AMD and that high beta-carotene intake was associated with an increased risk of AMD.
Studies on genetic determinants of AMD have developed slowly because (1) AMD is a disease of old age, surviving parents and well-established family trees are rare; (2) AMD is likely to be a complex disease with numerous etiological factors; (3) the completion of the Human Genome Project with the access to human genome sequence data was only 5 years ago. Instead of having a single contributory gene, a polygenic pattern with multiple genes of variable effect may be involved. Considerable evidence in family, twin and sibling studies exists and suggests a genetic basis of AMD. Several family studies have shown that patients with a family history of AMD are at increased risk (Seddon et al., 2007, Smith and Mitchell, 1998). Recently, Luo et al. identified 4764 AMD patients, analyzed the familial aggregation and estimated the magnitude of familial risks in a population-based cross-sectional and case–control study. The results showed that for AMD, the population-attributable risk (PAR) for a positive family history was 0.34. Recurrence risks in relatives indicate increased relative risks in siblings (2.95), first cousins (1.29), second cousins (1.13), and parents (5.66) of affected cases (Luo et al., 2008). Many linkage and association studies have indicated that the most replicated signals reside on chromosome 1q25–31 and 10q26 (Fisher et al., 2005, Jakobsdottir et al., 2005, Klein et al., 1998, Majewski et al., 2003). We will discuss the genetic factors underlying AMD pathology further in the “single nucleotide polymorphisms” and “molecular pathology of AMD” sections below.
In this article, we review the histopathologic findings that define AMD, along with new molecular pathologic findings that have advanced our understanding of the molecular mechanisms of AMD pathogenesis.
Section snippets
Pathology of AMD
The progression of AMD occurs over an extended time frame, with the incidence of the disease increasing dramatically over the age of 70. AMD is a multifactorial disease that affects primarily the photoreceptors and RPE, Bruch's membrane, and choriocapillaries. Aging is associated with changes in the retina, including alterations in RPE cellular size and shape, thickening of Bruch's membrane, thickening of the internal limiting membrane, and a decrease in retinal neuronal elements (Green, 1996).
Single nucleotide polymorphism
With the sequencing of the human genome and improved DNA sequencing and mapping technologies, recent years have seen an explosion of genetic studies identifying single nucleotide polymorphisms (SNPs) which confer increased or decreased risk of disease (Smith, 2005). AMD is no exception, as SNPs associated with inflammation, oxidative stress, angiogenesis, and other pathological processes have been linked to AMD. Investigation of the expression of these genes and their functional properties in
Involvement of inflammatory cells
AMD is a multifactorial disease that affects primarily the photoreceptors and RPE cells. The RPE cell is a specialized neural cell originated from neuroectoderm that provides metabolic support mainly to photoreceptor cells and is close to the inner thin basal membrane of the Bruch's membrane, which interposed between the RPE and choriocapillaries. In normal eye physiology, the cells of the RPE are essential for the maintenance of retinal homeostasis. Both photoreceptors and RPE cells exhibit
Summary
AMD is a debilitating disease of the retina, which manifests clinically with loss of central vision and pathologically with the accumulation of drusen, RPE degeneration, photoreceptor atrophy, and in some cases, with CNV. While several risk factors, including age, race, smoking, and diet have been linked to AMD, the etiology and pathogenesis of the disease remain largely unclear. Treatment options for the condition are similarly limited. As the prevalence of this already widespread disease
Future direction
Though AMD research has made great advances in recent years, our understanding of its pathogenesis remains largely incomplete. Given the context specificity of many critical biological processes and the fact that most common diseases including AMD are thought to be the outcome of a complex interaction between many genetic loci and the environment, it follows that there are obvious advantages to studying gene expression in cells and tissues that represent the in vivo state. For example, in a
Acknowledgments
We would like to thank Dr. Robert B. Nussenblatt for his critical review. The support for this study was provided by the NEI Intramural Research Program.
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