Age-related macular degeneration (AMD) develops under the background of senescent alterations accumulating over decades, followed by early AMD findings including drusen. Many people aged ≥50 years are at a high risk of developing this disease. While wet AMD is currently treatable with anti-vascular endothelial growth factor (VEGF) therapy and photodynamic therapy that target macular neovascularization, there are several problems, such as limited treatment efficacy, complications, and economic burden. Ideally, the incidence of AMD should be prevented. Additionally, new treatment modalities to address the current issues (e.g., frequent injections of anti-VEGF drugs) and to prevent macular atrophy and fibrotic scarring, which are the main causes of irreversible vision loss, are needed. To develop a new prophylactic or therapeutic approach, the pathogenesis of AMD should be elucidated. To do so, the physiological functions of the retinal pigment epithelium (RPE), which plays a pivotal role in the pathogenesis of AMD, and senescent changes related to the physiological functions of RPE cells must be understood.
The accumulation of lipofuscin granules in RPE cells, the first senescent change in the eye, was simulated in rabbit eyes using artificially-prepared imitation lipofuscin granules. This rabbit model of lipofuscin accumulation could reproduce hard drusen and exhibit abnormal fundus autofluorescence, choroidal neovascularization, and geographic atrophy. Transmission electron microscopy revealed that the hard drusen was composed of the cytoplasm of RPE cells, suggesting that the accumulation of lipofuscin granules in the cytoplasm of RPE cells mechanically impairs budding behavior, resulting in drusen formation. Next, we developed a 3-dimensional culture system to produce RPE spheroids. When RPE cells were cultured with methylcellulose-containing culture medium in 96-well culture plates with a U-shaped bottom, the seeded cells promptly aggregated to form a spheroid. The inside cells lead to apoptosis and the monolayer of RPE cells was formed at the outside of the spheroid, making the surface contacting the serum a basement membrane side. This monolayer had the Bruch membrane-like structure involving elastic fiber and type I and IV collagen at the outermost surface. Using this culture system, the mechanism of Bruch membranogenesis was clarified, which includes the following four steps: (1) high level of calcium ion in the serum may stimulate calcium channels and calcium-activated chloride channels, which are involved in the pathogenesis of Best disease, and enhance lamellipodial crawling covering the surface of spheroids; (2) RhoA-ROCK activation may result in purse-string contraction of actin filaments of the lamellipodia, driving spherical formation; (3) tropoelastin granules in the lamellipodia and deposition of type IV collagen fibrils between RPE cells and lamellipodia may form the elastin layer and the basement membrane, respectively; and (4) type I collagen fibrils may be deposited, leading to the maturation of the Bruch membrane. The RPE may secrete lipoproteins derived from phagocytosed outer segments of photoreceptors synchronously with the remodeling of the Bruch membrane through the abovementioned functions. The overload of lipofuscin granules may mechanically impair lamellipodial behavior, resulting in the formation of hard drusen (volume stress theory). The accumulation of lipofuscin granules becomes prominent in the 30s and later, which supposedly triggers the accumulation of lipoproteins under the RPE, the second senescent change. The membranous debris observed in the Bruch membrane of aging eyes may be derived from RPE plasma membrane, which is deposited by budding and shedding to reduce volume stress. Furthermore, complement activation may be associated with these membranous debris. Amyloid β may be associated with lipoprotein secretion. Accumulated lipoproteins may be oxidized, inducing oxidative stress and concomitant chronic inflammation. Mast cells may be used for the remodeling of the Bruch membrane, while macrophages may eliminate oxidized lipids, resulting in the onset of AMD.
Disease types (pachychoroid spectrum disease, typical AMD, retinal angiomatous proliferation, and dry AMD) may be determined by the balance of lipid accumulation under the RPE, upregulated VEGF secretion, and the impairment of the barrier function of RPE. Furthermore, the pathology may be complicated by RPE atrophy, which reduces VEGF secretion but further impairs the barrier function.
In this review, we summarize the interaction among photoreceptors, the RPE, and choriocapillaris, the physiology of the RPE, and aging-related changes in and around the RPE. Additionally, we propose our own hypothesis regarding the pathogenesis of AMD and Best disease and the biogenesis of various drusen and abnormal autofluorescence.
Nippon Ganka Gakkai Zasshi (J Jpn Ophthalmol Soc) 127: 329-366, 2023.