Aging, age-related macular degeneration, and the response-to-retention of apolipoprotein B-containing lipoproteins

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Abstract

The largest risk factor for age-related macular degeneration (ARMD) is advanced age. A prominent age-related change in the human retina is the accumulation of histochemically detectable neutral lipid in normal Bruch's membrane (BrM) throughout adulthood. This change has the potential to have a major impact on physiology of the retinal pigment epithelium (RPE). It occurs in the same compartment as drusen and basal linear deposit, the pathognomonic extracellular, lipid-containing lesions of ARMD. Here we present evidence from light microscopic histochemistry, ultrastructure, lipid profiling of tissues and isolated lipoproteins, and gene expression analysis that this deposition can be accounted for by esterified cholesterol-rich, apolipoprotein B-containing lipoprotein particles constitutively produced by the RPE. This work collectively allows ARMD lesion formation and its aftermath to be conceptualized as a response to the retention of a sub-endothelial apolipoprotein B lipoprotein, similar to a widely accepted model of atherosclerotic coronary artery disease (CAD) (Tabas et al., 2007). This approach provides a wide knowledge base and sophisticated clinical armamentarium that can be readily exploited for the development of new model systems and the future benefit of ARMD patients.

Section snippets

Statement of scope

Age-related macular degeneration (ARMD) is a major cause of vision loss in the elderly of the industrialized world. The largest risk factor for ARMD is advanced age. One of the most prominent age-related changes to the human retina is the accumulation of histochemically detectable neutral lipid in normal Bruch's membrane (BrM) throughout adulthood (Pauleikhoff et al., 1990). Arguably one the most important observations relevant to ARMD pathobiology, the Pauleikhoff study indicated that a

Introduction to outer retina and choroid (Fig. 1)

The 100 million rod and cone photoreceptors located at the outer surface of the retinal sheet are supported by the RPE. This polarized monolayer serves diverse functions essential for optimal photoreceptor health, including daily phagocytosis of photoreceptor outer segment tips, vitamin A metabolism, maintenance of retinal attachment, and coordination of cytokine-mediated immune protection. While inner retinal layers rely on the intrinsic retinal circulation, the photoreceptors and RPE depend

Epidemiology and risk factors

While responsible for high-acuity vision, the macula is also vulnerable to ARMD, the major cause of vision loss among elderly of European derivation living in industrialized societies (Congdon et al., 2004). RPE cell death across the macula (geographic atrophy) is a slow but devastating loss of vision (“dry” ARMD). Some patients at early to intermediate stages of dry ARMD can benefit from supplementation with an anti-oxidant mixture (2001a). Choroidal neovascularization, an invasion of

Neutral lipids accumulate with age in BrM (Fig. 3)

Clinical observations on the natural history of serous (fluid-filled) RPE detachments in older adults led to the hypothesis by Bird and colleagues that a lipophilic barrier in BrM blocked the normal outwardly-directed fluid efflux from the RPE (Bird and Marshall, 1986). Impaired movement of fluid from RPE or from leaky vessels in choroidal neovascular membranes was thought to contribute to the formation of RPE detachments in ARMD patients (Marshall et al., 1998). Lipophilic material in BrM, if

Cholesterol and its forms (Fig. 4A)

A hydrophobic alcohol built up from condensations of isoprene units, cholesterol is an essential component of all animal cell membranes (Fliesler and Keller, 1997) (Fig. 4A). Cholesterol exists in two chemical forms and three physical forms. The two chemical forms are unesterified (UC) or bound by an ester linkage to a fatty acid at the 3-beta-hydroxy group to produce esterified cholesterol (EC). The three physical forms are differentiated by the relative proportions of UC, EC, and solubilizing

Cholesterol in aged BrM – histochemical, physicochemical studies (Fig. 6)

Lipids that bind the histochemical stain oil red O increase with age in normal human connective tissues, including the sclera (Broekhuyse, 1972), cornea (Gaynor et al., 1996), intima of large arteries (Smith, 1974), and BrM (Pauleikhoff et al., 1990). In the intima, the oil red O-positive material comprises small (60–200 nm) extracellular droplets highly enriched in EC relative to UC (69% EC, 22% UC, and 9% PL) (Bocan et al., 1986, Chao et al., 1990, Guyton and Klemp, 1988, Guyton and Klemp, 1989

EC-rich barrier in aged BrM; Lipid Wall (Figs. 8–10)

As revealed by QFDE analysis of normal eyes of different ages (Huang et al., 2007b, Huang et al., 2008a, Ruberti et al., 2003), significant lipoprotein accumulation begins during the third or fourth decade of life in or near the elastic layer of macular BrM. This process is reminiscent of the preferential deposition of lipoprotein-derived EC near elastin in arterial intima (Guyton et al., 1985). With advancing age, following the elastic layer becoming filled with these particles and other

Cholesterol and apolipoproteins in sub-RPE lesions

Here we consider the cholesterol and apolipoproteins in the extracellular sub-RPE lesions associated with aging and ARMD (Section 3.2 for definitions and descriptions). Lesion composition is best known for drusen, which are amenable both for histochemistry in tissue sections and for isolation and direct assay. The relationship between normal aging and an ARMD-specific lesion may be best appreciated for the Lipid Wall and BlinD. The latter may be more correctly described as containing

Response-to-retention of an intra-ocular apoB lipoprotein

Our view of the role of BlinD and soft drusen in ARMD pathogenesis and progression centers around three concepts: 1) a barrier that prevents aqueous phase nutrients in plasma (Pauleikhoff et al., 1990) or other compounds with potential for clearance (e.g., HDL) from gaining access to RPE, thus obstruction the elimination of waste products; 2) a plane that sequesters angiogenic compounds, cytokines, modified lipids, or proteins (Crabb et al., 2002, Spaide et al., 1999, Yamada et al., 2008) that

Directions for laboratory research

The central role of RPE and BrM in ARMD pathogenesis has been recognized for almost 4 decades (Hogan, 1972). The studies reviewed herein have major implications for research in RPE cell biology, as information about the homeostasis of cholesterol and neutral lipid in this polarized epithelium and its supporting basement membrane is surprisingly sparse. While a connection between age-related lipid accumulation in BrM and ARMD was postulated 2 decades ago, many questions remain. Why does lipid

Conclusion

We have presented a body of work strongly implicating the RPE as constitutive secretor of EC-rich apoB-lipoproteins which when retained and accumulated in BrM contributes importantly to impeding RPE and photoreceptor function and to forming the specific lesions of ARMD. The conceptual framework, borrowed heavily from decades of atherosclerosis research, provides a wide knowledge base and sophisticated clinical armamentarium that can be readily exploited for the benefit of ARMD patients.

Acknowledgments

We are grateful for support from NIH grants EY06109 and EY014662, International Retinal Research Foundation, American Health Assistance Foundation, EyeSight Foundation of Alabama, Research to Prevent Blindness, Inc., Macula Vision Research Foundation, Roger Johnson Prize in Macular Degeneration Research, and Deutsche Forschungsgemeinschaft. CAC thanks especially the Alabama Eye Bank, members of Lipid Breakfast (Atherosclerosis Research Unit, J.P. Segrest, MD, PhD, Director, Department of

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