Esterified and unesterified cholesterol in drusen and basal deposits of eyes with age-related maculopathy

Curcio, Christine A.; Presley, Jennifer B.; Malek, Goldis; Medeiros, Nancy E.; Avery, D; Kruth, Howard S.

doi:10.1016/j.exer.2005.04.012

Cited by 226 publications

(207 citation statements)

References 37 publications

Supporting

Mentioning

194

Contrasting

Order By: Relevance

“…The presence of cholesterol and CE deposits in the Bruch's membrane of AMD eyes (9,10) and the correlation of genetic variations in cholesterol transporters with AMD susceptibility (12,13) point to an age-related alteration in cholesterol homeostasis in the RPE that may contribute to AMD progression. In this context, it is noteworthy that cholesterol and CE deposits in the Bruch's membrane are thought to originate from the RPE, including incompletely processed OS and additional sources such as the RPE itself (9).…”

Section: Discussionmentioning

confidence: 99%

“…In this context, it is noteworthy that cholesterol and CE deposits in the Bruch's membrane are thought to originate from the RPE, including incompletely processed OS and additional sources such as the RPE itself (9). Because our data demonstrate that A2E causes a Ͼ4-fold increase in LE/Ly free cholesterol (apart from CE accumulation), and because membranous debris beneath the RPE appear to originate as blebs and/or exocytosed organelles from the RPE basal surface (33,34), it is tempting to speculate that the source of subRPE cholesterol/CE deposits could be LE/Ly internal membranes extruded from A2E-laden cells.…”

Section: Discussionmentioning

confidence: 99%

“…Progressive lipid and cholesterol accumulation in the Bruch's membrane beneath the RPE has been identified as a contributing factor to age-related macular degeneration (AMD) (5). Apolipoproteins, cholesterol and cholesteryl esters (CE) are abundant in both drusen (lipid-protein aggregates in the Bruch's membrane) and other subRPE deposits in AMD eyes (9)(10)(11), suggesting compromised cholesterol homeostasis in the RPE. Moreover, cardiovascular disease and allelic variants in apolipoprotein E and ATP-binding cassette protein A1 (ABCA1) have been linked to AMD susceptibility in humans (12,13).…”

Section: Proteins Involved In Cholesterol Traffickingmentioning

confidence: 99%

See 2 more Smart Citations

The lipofuscin fluorophore A2E perturbs cholesterol metabolism in retinal pigment epithelial cells

Lakkaraju

Finnemann

Rodríguez-Boulan

2007

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

148

145

View full text Add to dashboard Cite

Proteins involved in cholesterol trafficking are known to contribute to the pathogenesis of atherosclerosis and Alzheimer's disease. Allelic variants in the cholesterol transporters apolipoprotein E and ATP-binding cassette protein A1 (ABCA1) have recently been associated with susceptibility to age-related macular degeneration (AMD). Histopathological analyses of eyes with AMD demonstrate the presence of cholesterol and cholesteryl ester deposits beneath the retinal pigment epithelium (RPE), implicating abnormal cholesterol trafficking in disease progression. Here, we show that A2E, a quaternary amine and retinoid by-product of the visual cycle, causes the accumulation of free and esterified cholesterol in RPE cells. The mechanism involves neither generalized alterations in late endosomal/lysosomal pH nor a direct inhibition of acid lipase activity. Rather, A2E prevents cholesterol efflux from these organelles, which in turn indirectly inhibits acid lipase, leading to a subsequent accumulation of cholesteryl esters. Transcriptional activation of the ABCA1 cholesterol transporter by agonists of the liver X receptor/peroxisome proliferator-activated receptor pathway relieves the A2E-induced block on cholesterol efflux and restores cholesterol homeostasis in RPE cells. Our data also demonstrate that A2E, which is a cone-shaped lipid, increases the chemical activity and displacement of cholesterol from model membranes, providing a biophysical mechanism for cholesterol sequestration in A2E-loaded cells. Although endogenously produced A2E in the RPE has been associated with macular degeneration, the precise mechanisms are unclear. Our results provide direct evidence that A2E causes aberrant cholesterol metabolism in RPE cells which could likely contribute to AMD progression.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Proteins Involved In Cholesterol Traffickingmentioning

confidence: 99%

See 1 more Smart Citation

The lipofuscin fluorophore A2E perturbs cholesterol metabolism in retinal pigment epithelial cells

Lakkaraju

Finnemann

Rodríguez-Boulan

2007

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

148

145

View full text Add to dashboard Cite

show abstract

“…Clinically, a number of studies have also reported the association of dietary fats with AMD (Chong et al, 2006). Cholesterol and apoE make up sub-RPE deposits in AMD eyes (Curcio et al, 2005;Li et al, 2006a), and Apo-E4 targeted replacement mice on high fat and cholesterol rich diets developed drusen and CNV (Malek et al, 2005). However, the connection between dietary fat, lipids, and VEGF is less clear.…”

Section: 62mentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

636

527

View full text Add to dashboard Cite

Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

show abstract

“…[46][47][48][49][50] It has been suggested that macrophages play a role in removal of drusen and other waste products, perhaps preventing the severe end-stage pathology that can occur after the accumulation of these deposits. 51,52 Monocyte chemotactic protein-1 (MCP-1/CCL2) is a chemokine that directs monocyte recruitment into inflamed tissues.…”

Section: How Might Macrophages Promote Macular Degeneration?mentioning

confidence: 99%

Macrophages in neovascular age-related macular degeneration: friends or foes?

Skeie

Mullins

2008

Eye

View full text Add to dashboard Cite

The events that lead to choroidal neovascularization in eyes with age-related macular degeneration are poorly understood. One possibility that has been explored in a number of studies is that macrophages can promote neovascular changes. In this paper, we summarize the evidence for inflammation in general and macrophages in particular in pathologic neovascularization, and discuss how the diverse functions of these cells may promote or inhibit macular disease. We also discuss some of the conflicting findings regarding the role of macrophages in experimental choroidal neovascularization in mouse models, and suggest areas for future research.

show abstract

Esterified and unesterified cholesterol in drusen and basal deposits of eyes with age-related maculopathy

Cited by 226 publications

References 37 publications

The lipofuscin fluorophore A2E perturbs cholesterol metabolism in retinal pigment epithelial cells

The lipofuscin fluorophore A2E perturbs cholesterol metabolism in retinal pigment epithelial cells

Vascular endothelial growth factor in eye disease

Macrophages in neovascular age-related macular degeneration: friends or foes?

Contact Info

Product

Resources

About