REVIEW PAPER: Animals as Models of Age-Related Macular Degeneration

Abstract

Age-related macular degeneration (AMD) is a degenerative condition that begins in Bruch's membrane and progresses to involve the retinal pigment epithelium and ultimately the overlying photoreceptors. The only required etiologic factor is age, and AMD is regarded as the leading cause of blindness in individuals older than 65 years. AMD results from variable contributions of age, environment, and genetic predisposition. Many loci are linked to AMD; in the majority of cases, the disease is associated with polymorphisms within these genes, rather than mutations that ablate gene function. The etiologic complexity of AMD is reflected by the paucity of animal models that entirely replicate the human disease. This review compares the salient anatomy of the primate and rodent retina, particularly in the light of AMD pathology. It next discusses prevailing hypotheses explaining how AMD may develop. These include the role of complement activation and macrophage chemotaxis in AMD, molecular mechanisms of choroidal neovascularization, and the roles of oxidative damage and lipid metabolism. Finally, the article gives an overview of spontaneous and induced nonhuman primate models and describes relevant mouse models in the context of each pathogenetic mechanism. KeywordsBruch's membrane, choriocapillaris, complement, degeneration, macula, retinal pigment epithelium Age-related macular degeneration (AMD) is a progressive condition of the retinal pigment epithelium (RPE), its supporting basement membrane, and the overlying photoreceptor layer. It affects the macula, the central area of the retina responsible for high-acuity daylight vision. Among individuals older than 65 years, AMD is regarded as the leading cause of blindness in the industrialized world. 39AMD has no single cause and results from variable contributions of age, genetic predisposition, and environment. Established epidemiologic risk factors include cigarette smoking, diet, female sex, Caucasian race, and a family history of AMD.52,60,61 Because AMD is rare in individuals younger than 55 years, the only required risk factor is age, which implicates the multitude of cellular changes that accompany normal aging in the pathogenesis of AMD. The challenge is to identify how these are altered to tip the process toward overt disease.With age, most people accumulate small, well-demarcated deposits of extracellular material beneath the RPE. 5,45 These are known as small, hard drusen and are not pathogenic. However, if these deposits enlarge, they become associated with regional RPE loss and eventual degeneration of overlying photoreceptors. These changes are funduscopically visible, and their progression is used to classify lesions along the continuum of early to late dry AMD. 18 The pathogenetic mechanisms of this process center on inflammation, oxidative damage, and RPE senescence 45 and are predominantly modeled in the mouse.In the minority of cases, late AMD is accompanied by growth of blood vessels from the choroid through Bruch's membrane toward the retina. ...

Regulation of age-related macular degeneration-like pathology by complement factor H

“…This idea is supported by data showing that the double-transgenic Cfh −/− , C3 −/− retinal phenotype is similar to the phenotype observed in C3 −/− or Cfh −/− mice (60). In contrast, the Cfh +/− ∼HFC mice we have characterized here display a robust AMD-like ocular phenotype, with substantial sub-RPE deposit formation, multinucleate RPE and atrophy, photoreceptor cell loss, and visual function decline (61, 62). It should be noted that nearly 10% of sub-RPE deposits were greater than 4 μm in height, which represents the largest deposits detected in any AMD mouse model within our laboratory; comparisons to other studies is difficult due to the lack of systematic quantification and the use of younger mice (38, 58, 60, 63–71).…”

“…Thus, our data show that sub-RPE deposit formation occurs with the combination of diet and CFH deficiency before RPE/photoreceptor dysfunction. Furthermore, it is important to note that the cornerstones of the Cfh +/− ∼HFC model are predominant factors established within the human disease: advanced age, genetic alteration of CFH, complement dysregulation, and cholesterol/lipid metabolism perturbation (15, 61, 62). …”

Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism

“…Despite evidence converging on the role of energy deregulation, surprisingly little is known about the energy signals that may govern AMD. Few suitable animal models replicate all aspects of AMD, but several transgenic mice present some characteristic signs of the disease (Table 1) (Ambati et al, 2003; Baba et al, 2010; Cao et al, 2010; Cashman et al, 2011; Chen et al, 2007; Combadière et al, 2007; Hahn et al, 2004; Heckenlively et al, 2003; Imamura et al, 2006; Jo et al, 2011; Luhmann et al, 2009; Lyzogubov et al, 2011; Malek et al, 2005; Markovets et al, 2011; Shen et al, 2006; Takada et al, 1994; Tuo et al, 2007; Zeiss, 2010; Zhao et al, 2011b). …”

Investigating the influence of chromatic aberration and optical illumination bandwidth on fundus imaging in rats

“…[1][2][3][4] Rodent models provide cost-effective ways to investigate the pathogenesis and therapeutic strategies in visual impairing diseases, such as macular degeneration, diabetic retinopathy, and glaucoma. [5][6][7] Histological examination is commonly used to visualize subtle structural and functional changes in retinal tissue during disease progressions and treatments. 8 However, histological examinations are limited to terminal studies.…”