Aging, age-related macular degeneration, and the response-to-retention of apolipoprotein B-containing lipoproteins
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
References (339)
- et al.
A rapid method for staining large chylomicrons
J. Lipid Res.
(1989) - et al.
Local cellular sources of apolipoprotein E in the human retina and retinal pigmented epithelium: implications for the process of drusen formation
Am. J. Ophthalmol.
(2001) - et al.
A role for local inflammation in the formation of drusen in the aging eye
Am. J. Ophthalmol.
(2002) - et al.
Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration
Exp. Eye Res.
(2004) - et al.
A simple, rapid, and sensitive fluorescence assay for microsomal triglyceride transfer protein
J. Lipid Res.
(2004) - et al.
Evidence that the death of macrophage foam cells contributes to the lipid core of atheroma
Atherosclerosis
(1995) - et al.
Transplantation of the RPE in AMD
Prog. Retin. Eye Res.
(2007) - et al.
Lipoprotein secretion and triglyceride stores in the heart
J. Biol. Chem.
(2001) - et al.
Relationship of cholesterol content to spatial distribution and age of disk membranes in retinal rod outer segments
J. Biol. Chem.
(1990) - et al.
Lipid and fatty acid profile of the retina, retinal pigment epithelium/choroid, and the lacrimal gland, and associations with adipose tissue fatty acids in human subjects
Exp. Eye Res.
(2008)
Lipids in tissues of the eye. VII. Changes in concentration and composition of sphingomyelins, cholesterol esters and other lipids in aging sclera
Biochim. Biophys. Acta
Association of apo B lipoproteins with arterial proteoglycans: pathological significance and molecular basis
Atherosclerosis
Lipoprotein lipase in highly vascularized structures of the eye
J. Lipid Res.
Lipid efflux by the ATP-binding cassette transporters ABCA1 and ABCG1
Biochim. Biophys. Acta
Oxidized LDL bind to nonproteoglycan components of smooth muscle extracellular matrices
J. Lipid Res.
Phosphatidylcholine-rich acceptors, but not native HDL or its apolipoproteins, mobilize cholesterol from cholesterol-rich insoluble components of human atherosclerotic plaques
Biochem. Biophys. Acta Mol. Cell Biol. Lipids
The role of aging, high fat diet and blue light exposure in an experimental mouse model for basal laminar deposit formation
Exp. Eye Res.
Ocular lipid deposition and hyperlipoproteinaemia
Prog. Retin. Eye Res.
Imaging maculopathy in the post-mortem human retina
Vis. Res.
Peripapillary chorioretinal atrophy: bruch's membrane changes and photoreceptor loss
Ophthalmology
Esterified and unesterified cholesterol in drusen and basal deposits of eyes with age-related maculopathy
Exp. Eye Res.
Basal deposits and drusen in eyes with age-related maculopathy: evidence for solid lipid particles
Exp. Eye Res.
Human retinal pigment epithelial cells express scavenger receptors BI and BII
Biochem. Biophys. Res. Commun.
Xanthophylls are preferentially taken up compared to beta -carotene by retinal cells via a scavenger receptor BI-dependent mechanism
J. Lipid Res.
Melanin binds reversibly to thermostable DNA polymerase and inhibits its activity
Biochem. Biophys. Res. Commun.
Age-related changes in the ultrastructure of Bruch's membrane
Am. J. Ophthalmol.
Complexity in the secretory pathway: the assembly and secretion of apolipoprotein B-containing lipoproteins
J. Biol. Chem.
Isoprenoid metabolism in the vertebrate retina
Int. J. Biochem. Cell Biol.
Electron microscopy of negatively stained lipoproteins
Methods Enzymol.
Ultrastructure of the intima in WHHL and cholesterol-fed rabbit aortas prepared by ultra-rapid freezing and freeze-etching
J. Lipid Res.
A human apoB100 transgenic mouse expresses human apoB100 in the RPE and develops features of early AMD
Exp. Eye Res.
Cholesterol accumulation in human cornea: evidence that extracellular cholesteryl ester-rich lipid particles deposit independently of foam cells
J. Lipid Res.
Focus on Molecules: interphotoreceptor retinoid-binding protein (IRBP)
Exp. Eye Res.
Progress towards understanding the role of microsomal triglyceride transfer protein in apolipoprotein-B lipoprotein assembly
Biochim. Biophys. Acta
Age-related macular degeneration histopathologic studies: the 1992 Lorenz E. Zimmerman Lecture
Ophthalmology
2001a. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. AREDS Report No. 8
Arch. Ophthalmol.
2001b. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III)
JAMA
Lipid histochemistry
Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome
Arterioscler. Thromb. Vasc. Biol.
Improving RPE adhesion to Bruch's membrane
Eye
The concept of apolipoprotein-defined lipoprotein families and its clinical significance
Curr. Atheroscler. Rep.
Drusenoid lesions and lipid-filled retinal pigment epithelium cells in a rhesus macula
Vet. Ophthalmol.
The ultrastructure of the pigment epithelium and of the photoreceptor-pigment epithelium interface
J. Ultrastruct. Res.
Lipids in human lipofuscin-enriched subcellular fractions of two age population
Invest. Ophthalmol. Vis. Sci.
Docosahexaenoic acid uptake and metabolism in photoreceptors: retinal conservation by an efficient retinal pigment epithelial cell-mediated recycling process
Adv. Exp. Med. Biol.
The role of the microsomal triglyceride transfer protein in abetalipoproteinemia
Annu. Rev. Nutr.
Retinal pigment epithelial detachments in the elderly
Trans. Ophthalmol. Soc. UK
Brain cholesterol: long secret life behind a barrier
Arterioscler Thromb. Vasc. Biol.
Ultrastructure of the human aortic fibrolipid lesion. Formation of the atherosclerotic lipid-rich core
Am. J. Pathol.
Clinicopathological correlation of drusen and retinal pigment epithelial abnormalities in age-related macular degeneration
Retina
Cited by (214)
Role of immune inflammation regulated by macrophage in the pathogenesis of age-related macular degeneration
2024, Experimental Eye ResearchUltrahigh Resolution OCT Markers of Normal Aging and Early Age-related Macular Degeneration
2023, Ophthalmology ScienceInside out: Relations between the microbiome, nutrition, and eye health
2022, Experimental Eye ResearchChoriocapillaris: Fundamentals and advancements
2022, Progress in Retinal and Eye Research