Age-related Macular Degeneration Histopathologic Studies

Green, W. Richard; Enger, Cheryl

doi:10.1016/s0161-6420(93)31466-1

Cited by 662 publications

(241 citation statements)

References 55 publications

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“…Although EFEMP1 is expressed in many nonocular tissues as well as in the retina (70), this is the first documented mutation known to result in the accumulation of extracellular debris (drusen) below the retinal pigment epithelium. Drusen have been long known to be an important risk factor for age-related macular degeneration (22,71). Drusen formation associated with a mutation in an EGF-like module in EFEMP1 suggests that mutations in other genes coding for molecules containing EGF-like modules may also be causally related to drusen formation.…”

Section: Expression and Localization Of Spacrcan-mentioning

confidence: 99%

SPACRCAN, a Novel Human Interphotoreceptor Matrix Hyaluronan-binding Proteoglycan Synthesized by Photoreceptors and Pinealocytes

Acharya¹,

Foletta²,

Lee³

et al. 2000

Journal of Biological Chemistry

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The interphotoreceptor matrix is a unique extracellular complex occupying the interface between photoreceptors and the retinal pigment epithelium in the fundus of the eye. Because of the putative supportive role in photoreceptor maintenance, it is likely that constituent molecules play key roles in photoreceptor function and may be targets for inherited retinal disease. In this study we identify and characterize SPACRCAN, a novel chondroitin proteoglycan in this matrix. SPACRCAN was cloned from a human retinal cDNA library and the gene localized to chromosome 3q11.2. Analysis of SPACRCAN mRNA and protein revealed that SPACRCAN is expressed exclusively by photoreceptors and pinealocytes. SPACRCAN synthesized by photoreceptors is localized to the interphotoreceptor matrix where it surrounds both rods and cones. The functional protein contains 1160 amino acids with a large central mucin domain, three consensus sites for glycosaminoglycan attachment, two epidermal growth factor-like repeats, a putative hyaluronan-binding motif, and a potential transmembrane domain near the C-terminal. Lectin and Western blotting indicate an M r around 400,000 before and 230,000 after chondroitinase ABC digestion. Removal of N-and O-linked oligosaccharides reduces the M r to approximately 160,000, suggesting that approximately 60% of the mass of SPACRCAN is carbohydrate. Finally, we demonstrate that SPACRCAN binds hyaluronan and propose that associations between SPACRCAN and hyaluronan may be involved in organization of the insoluble interphotoreceptor matrix, particularly as SPACRCAN is the major proteoglycan present in this matrix.

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Section: Expression and Localization Of Spacrcan-mentioning

confidence: 99%

SPACRCAN, a Novel Human Interphotoreceptor Matrix Hyaluronan-binding Proteoglycan Synthesized by Photoreceptors and Pinealocytes

Acharya¹,

Foletta²,

Lee³

et al. 2000

Journal of Biological Chemistry

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“…Occasional breaks in Bruch's membrane with accompanying neovascularization also have been reported, although BMD is not noted for extensive choroidal neovascularization. Many of these features also are found in AMD (11)(12)(13).…”

mentioning

confidence: 92%

Bestrophin, the product of the Best vitelliform macular dystrophy gene ( VMD2 ), localizes to the basolateral plasma membrane of the retinal pigment epithelium

Marmorstein

Rayborn

et al. 2000

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

393

329

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Best vitelliform macular dystrophy is a dominantly inherited, early onset, macular degenerative disease that exhibits some histopathologic similarities to age-related macular degeneration. Although the vitelliform lesion is common in the fundus of individuals with Best disease, diagnosis is based on a reduced ratio of the light peak to dark trough in the electrooculogram. Recently, the VMD2 gene on chromosome 11q13, encoding the protein bestrophin, was identified. The function of bestrophin is unknown. To facilitate studies of bestrophin, we produced both rabbit polyclonal and mouse monoclonal antibodies that proved useful for Western blotting, immunoprecipitation, and immunocytochemistry. To characterize bestrophin, we initially probed the retinal pigment epithelium (

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“…Photooxidative stress, photoreceptor outer segment shedding, lipid peroxidation, high metabolic requirements, and increased oxygen demand result in high levels of oxidative stress to the fundus. As a result, with aging, the RPE and choriocapillaris endothelium dedifferentiate (5,6). The most significant changes are basal deposits that develop within BM, a pentalaminar matrix that includes the RPE and choriocapillaris endothelial basement membrane (5,6).…”

mentioning

confidence: 99%

“…As a result, with aging, the RPE and choriocapillaris endothelium dedifferentiate (5,6). The most significant changes are basal deposits that develop within BM, a pentalaminar matrix that includes the RPE and choriocapillaris endothelial basement membrane (5,6). The location and composition of the deposits correlates with the development of age-related disease (5,6).…”

mentioning

confidence: 99%

“…The most significant changes are basal deposits that develop within BM, a pentalaminar matrix that includes the RPE and choriocapillaris endothelial basement membrane (5,6). The location and composition of the deposits correlates with the development of age-related disease (5,6). The molecular events surrounding basal deposit formation, however, are poorly characterized.…”

mentioning

confidence: 99%

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Advanced glycation endproduct-induced aging of the retinal pigment epithelium and choroid: A comprehensive transcriptional response

Tian

Ishibashi

et al. 2005

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

115

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Advanced glycation endproduct (AGE) formation is a trigger for the onset of age-related disease. To evaluate AGE-induced change in the ocular fundus, 5-mo-old C57BL͞6 mice were given low-dose D-galactose (D-gal) for 8 wk and evaluated by AGE fluorescence, electroretinography (ERG), electron microscopy, and microarray analysis for 20 wk. Although AGE fluorescence was increased in D-gal-treated retinal pigment epithelium (RPE)-choroid compared with controls at all time points, ERG showed no AGE-induced functional toxicity. Progressive ultrastructural aging in the RPEchoroid was associated temporally with a transcriptional response of early inflammation, matrix expansion, and aberrant lipid processing and, later, down-regulation of energy metabolism genes, up-regulation of crystallin genes, and altered expression of cell structure genes. The overall transcriptome is similar to the generalized aging response of unrelated cell types. A subset of transcriptional changes is similar to early atherosclerosis, a chronic inflammatory disease characterized by matrix expansion and lipid deposition. These changes suggest an important contribution of a single environmental stimulus to the complex aging response.transcriptome ͉ basal deposit ͉ Bruch's membrane A ging is a multifactorial process associated with physiological decline. Prior efforts to comprehensively identify and evaluate contributory factors have benefited from global assessment strategies such as microarray analysis. Although some general trends in the transcriptional responses to aging have been identified in diverse tissues such as skeletal muscle, cardiac muscle, and brain, the aging kidney is without modification (1-4).Normal vision requires a functional retinal pigment epithelium (RPE)-Bruch's membrane (BM)-choroid to sustain the neurosensory retina. Photooxidative stress, photoreceptor outer segment shedding, lipid peroxidation, high metabolic requirements, and increased oxygen demand result in high levels of oxidative stress to the fundus. As a result, with aging, the RPE and choriocapillaris endothelium dedifferentiate (5, 6). The most significant changes are basal deposits that develop within BM, a pentalaminar matrix that includes the RPE and choriocapillaris endothelial basement membrane (5, 6). The location and composition of the deposits correlates with the development of age-related disease (5, 6). The molecular events surrounding basal deposit formation, however, are poorly characterized.Advanced glycation endproducts (AGEs) are a heterogeneous group of reaction products that form between a protein's primary amino group and a carbohydrate-derived aldehyde group. A substantial amount of literature indicates that AGEs exacerbate and accelerate aging change and contribute to the early phases of age-related disease, including atherosclerosis, cataract, neurodegenerative disease, renal failure, arthritis, and age-related macular degeneration (AMD) (7,8). We found that AGEs accumulate with age in human BM and immunolocalize to basal deposits (9-11). We...

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Age-related Macular Degeneration Histopathologic Studies

Cited by 662 publications

References 55 publications

SPACRCAN, a Novel Human Interphotoreceptor Matrix Hyaluronan-binding Proteoglycan Synthesized by Photoreceptors and Pinealocytes

SPACRCAN, a Novel Human Interphotoreceptor Matrix Hyaluronan-binding Proteoglycan Synthesized by Photoreceptors and Pinealocytes

Bestrophin, the product of the Best vitelliform macular dystrophy gene ( VMD2 ), localizes to the basolateral plasma membrane of the retinal pigment epithelium

Advanced glycation endproduct-induced aging of the retinal pigment epithelium and choroid: A comprehensive transcriptional response

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