Formation of Drusen in the Human Eye

Ishibashi, Tatsuro; Patterson, Randi; Ohnishi, Yoshitaka; Inomata, Hajime; Ryan, Stephen J.

doi:10.1016/0002-9394(86)90830-5

Cited by 106 publications

(53 citation statements)

References 7 publications

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“…62 The process of RPE cell membrane blebbing and cytoplasm extrusion into Bruch's membrane may contribute to drusen formation. 56,65,66 This finding has been described in age-related macular degenera tion66 and in aged human eyes6 7 and is an expected finding in cells which contain excessive amounts of lysosomotropic detergent such as the recently identified lipofuscin fluorophore N-retinylidene-N retinylethanolamine. 1 3 Fundus flavimaculatus (Stargardt's disease) and vitelliform macular degeneration (Best's macular dystrophy) are two RPE diseases of unknown aetiology associated with abnormal accumulation of lipofuscin in the RPE cells.…”

Section: Relation To Retinal Diseasementioning

confidence: 61%

Lipofuscin of the retinal pigment epithelium: A review

Kennedy

Rakoczy

Constable

1995

Eye

326

209

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Section: Relation To Retinal Diseasementioning

confidence: 61%

Lipofuscin of the retinal pigment epithelium: A review

Kennedy

Rakoczy

Constable

1995

Eye

326

209

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“…Small vesicular structures have been identified in previous ultrastructural studies of drusen (11,(37)(38)(39)(40). Most notably, Ulshafer et al (41) identified two types of substructural elements: irregular globular masses and spherical entities with electron dense cores surrounded by concentric layers of ''crystalline spicules.''…”

Section: Discussionmentioning

confidence: 77%

The Alzheimer's Aβ-peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration

Johnson

Leitner²,

Rivest³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

411

321

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Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in older individuals worldwide. The disease is characterized by abnormal extracellular deposits, known as drusen, that accumulate along the basal surface of the retinal pigmented epithelium. Although drusen deposition is common in older individuals, large numbers of drusen and͞or extensive areas of confluent drusen represent a significant risk factor for AMD. Widespread drusen deposition is associated with retinal pigmented epithelial cell dysfunction and degeneration of the photoreceptor cells of the neural retina. Recent studies have shown that drusen contain a variety of immunomodulatory molecules, suggesting that the process of drusen formation involves local inflammatory events, including activation of the complement cascade. Similar observations in Alzheimer's disease (AD) have lead to the hypothesis that chronic localized inflammation is an important element of AD pathogenesis, with significant neurodegenerative consequences. Accordingly, the amyloid beta (A␤) peptide, a major constituent of neuritic plaques in AD, has been implicated as a primary activator of complement in AD. Here we show that A␤ is associated with a substructural vesicular component within drusen. A␤ colocalizes with activated complement components in these ''amyloid vesicles,'' thereby identifying them as potential primary sites of complement activation. Thus, A␤ deposition could be an important component of the local inflammatory events that contribute to atrophy of the retinal pigmented epithelium, drusen biogenesis, and the pathogenesis of AMD. C urrent theories of Alzheimer's disease (AD) pathogenesis include inflammatory processes as significant contributors to the disease process (1). Chronic local inflammation, including both direct and bystander cell damage attributable to complement-mediated attack, exacerbates the effects of primary AD pathogenic stimuli. Amyloid beta (A␤) has been implicated in activation of the complement cascade (2) and is a major component of AD plaques, where it colocalizes with activated complement components, the C5b-9 membrane attack complex (MAC), acute phase reactants, and other inflammatory mediators (3-5).New evidence suggests that a strikingly similar, chronic local inflammatory component is also associated with the formation of drusen, the age-related extracellular deposits that are often linked with age-related macular degeneration (AMD) (6-9). AMD is a retinal degenerative disease that leads to loss of central vision, and affects 5-10% of the population over 60 years of age. Drusen form between the basal surface of an epithelial monolayer derived from neuroectoderm that is known as the retinal pigmented epithelium (RPE), and a basement membrane complex called Bruch's membrane (Fig. 1). Small numbers of drusen are present in the eyes of many older individuals; however, numerous and͞or confluent drusen are associated clinically with geographic atrophy of the RPE (10) and with a significantly increased risk of ...

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“…Although the cell death pathways in slowly progressive human AMD have not been fully characterized, histological studies demonstrated that the budding portion of the RPE into the drusen exhibits disintegration and disruption of the plasma membrane. 32 In addition, RPE cells overlying drusen show necrotic changes such as cellular enlargement and vacuole formation in early AMD patients. 33,34 These findings suggest that necrotic pathways may be crucial in RPE cell death in AMD.…”

Section: Discussionmentioning

confidence: 99%

Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration

et al. 2013

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There is no known treatment for the dry form of an age-related macular degeneration (AMD). Cell death and inflammation are important biological processes thought to have central role in AMD. Here we show that receptor-interacting protein (RIP) kinase mediates necrosis and enhances inflammation in a mouse model of retinal degeneration induced by dsRNA, a component of drusen in AMD. In contrast to photoreceptor-induced apoptosis, subretinal injection of the dsRNA analog poly(I : C) caused necrosis of the retinal pigment epithelium (RPE), as well as macrophage infiltration into the outer retinas. In Rip3 À / À mice, both necrosis and inflammation were prevented, providing substantial protection against poly(I : C)-induced retinal degeneration. Moreover, after poly(I : C) injection, Rip3 À / À mice displayed decreased levels of pro-inflammatory cytokines (such as TNF-a and IL-6) in the retina, and attenuated intravitreal release of high-mobility group box-1 (HMGB1), a major damage-associated molecular pattern (DAMP). In vitro, poly(I : C)-induced necrosis were inhibited in Rip3-deficient RPE cells, which in turn suppressed HMGB1 release and dampened TNF-a and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF-a and IL-6 production after poly(I : C) stimulation in RPE cells or macrophages. Therefore, programmed necrosis is crucial in dsRNA-induced retinal degeneration and may promote inflammation by regulating the release of intracellular DAMPs, suggesting novel therapeutic targets for diseases such as AMD.

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Formation of Drusen in the Human Eye

Cited by 106 publications

References 7 publications

Lipofuscin of the retinal pigment epithelium: A review

Lipofuscin of the retinal pigment epithelium: A review

The Alzheimer's Aβ-peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration

Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration

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