Advanced Glycation End Products in Age-related Macular Degeneration

Ishibashi, Tatsuro

doi:10.1001/archopht.116.12.1629

Cited by 172 publications

(97 citation statements)

References 22 publications

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“…Further, CML is present in soft drusen and adjacent RPE cells before the development of choroidal neovascularization, but not in control eyes. 103 Although the implication of these findings warrants further exploration, it is consistent with an etiologic role for oxidative stress in the pathogenesis of AMD.…”

Section: Waste Products Of Oxidative Processes In Amdmentioning

confidence: 65%

The Role of Oxidative Stress in the Pathogenesis of Age-Related Macular Degeneration

Beatty

Koh²,

Phil

et al. 2000

Survey of Ophthalmology

1,772

1,347

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Abstract. Age-related macular degeneration (AMD) is the leading cause of blind registration in the developed world, and yet its pathogenesis remains poorly understood. Oxidative stress, which refers to cellular damage caused by reactive oxygen intermediates (ROI), has been implicated in many disease processes, especially age-related disorders. ROIs include free radicals, hydrogen peroxide, and singlet oxygen, and they are often the byproducts of oxygen metabolism. The retina is particularly susceptible to oxidative stress because of its high consumption of oxygen, its high proportion of polyunsaturated fatty acids, and its exposure to visible light. In vitro studies have consistently shown that photochemical retinal injury is attributable to oxidative stress and that the antioxidant vitamins A, C, and E protect against this type of injury. Furthermore, there is strong evidence suggesting that lipofuscin is derived, at least in part, from oxidatively damaged photoreceptor outer segments and that it is itself a photoreactive substance. However, the relationships between dietary and serum levels of the antioxidant vitamins and age-related macular disease are less clear, although a protective effect of high plasma concentrations of ␣ -tocopherol has been convincingly demonstrated. Macular pigment is also believed to limit retinal oxidative damage by absorbing incoming blue light and/or quenching ROIs. Many putative risk-factors for AMD have been linked to a lack of macular pigment, including female gender, lens density, tobacco use, light iris color, and reduced visual sensitivity. Moreover, the Eye Disease Case-Control Study found that high plasma levels of lutein and zeaxanthin were associated with reduced risk of neovascular AMD. The concept that AMD can be attributed to cumulative oxidative stress is enticing, but remains unproven. With a view to reducing oxidative damage, the effect of nutritional antioxidant supplements on the onset and natural course of age-related macular disease is currently being evaluated. Age-related macular degeneration (AMD) is the leading cause of blind registration in the western world, 119 and its prevalence is likely to rise as a consequence of increasing longevity. 225 There is a general consensus that cumulative oxidative damage is responsible for aging, and may, therefore, play an important role in the pathogenesis of AMD. In this article, we review the literature germane to oxidative processes in the retina and examine the evidence for a causal link between oxidative stress and age-related macular degeneration.

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Section: Waste Products Of Oxidative Processes In Amdmentioning

confidence: 65%

The Role of Oxidative Stress in the Pathogenesis of Age-Related Macular Degeneration

Beatty

Koh²,

Phil

et al. 2000

Survey of Ophthalmology

1,772

1,347

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“…9 BrM and sub-RPE deposits contain glycosoaminoglycans [63][64][65][66] and advanced glycation end-products that could retain and modify lipoproteins, respectively. 67,68 Proteins associated with inflammation and complement activation are present in drusen. 69,70 ARMassociated choroidal neovascular membranes include macrophages and smooth muscle actin-positive cells.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein B in Cholesterol-Containing Drusen and Basal Deposits of Human Eyes with Age-Related Maculopathy

Malek

Guidry

et al. 2003

The American Journal of Pathology

244

212

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Lipids accumulate in Bruch's membrane (BrM), a specialized vascular intima of the eye, and in extracellular lesions associated with aging and age-related maculopathy (ARM). We tested the hypothesis that ARM and atherosclerotic cardiovascular disease share molecules and mechanisms pertaining to extracellular lipid accumulation by localizing cholesterol and apolipoprotein B (apo B) in BrM, basal deposits, and drusen. Human donor eyes were preserved <4 hours postmortem and cryosectioned. Sections were stained with traditional lipid stains and filipin for esterified and unesterified cholesterol or probed with antibodies to apo B, apo E, and apo C-III. Normal adult retinal pigment epithelium (RPE) was subjected to RT-PCR and Western blot analysis for apolipoprotein mRNA and protein. Esterified and unesterified cholesterol was present in all drusen and basal deposits of ARM and normal eyes. Both apo B and apo E but not apo C-III were found in BrM, drusen, and basal deposits. Age-related maculopathy (ARM) is the leading cause of new, untreatable vision loss in the elderly in Western societies. [1][2][3] As shown in Figure 1A, ARM involves the retinal pigment epithelium (RPE, cells dedicated to sustaining photoreceptor health), the choriocapillaris (the blood supply to photoreceptors and the RPE), and Bruch's membrane (BrM, a thin vascular intima between the RPE and choriocapillaris). 4,5 Early ARM is characterized by moderate vision loss associated with characteristic extracellular lesions. Lesions between the RPE basal lamina and BrM can be focal (drusen) or diffuse (basal linear deposits). A diffuse lesion between the RPE and its basal lamina is basal laminar deposit. The term "sub-RPE deposits" is used for the combination of drusen and basal deposits and "basal deposits" for the combination of basal laminar deposit and basal linear deposit. Late ARM is characterized by severe vision loss associated with extensive RPE atrophy with or without the sequelae of choroidal neovascularization, ie, in-growth of choriocapillaries through BrM and under the RPE in the plane of drusen and basal linear deposits. Because the causes of ARM are obscure, recent studies have sought molecules present in the affected tissues and characteristic lesions to identify biochemical pathways perturbed by disease. 6 An important but incompletely characterized component of BrM and sub-RPE deposits is lipids. Normal BrM accumulates lipids with age, and the accumulation of esterified and unesterified cholesterol (EC and UC)-containing particles is especially prominent in the macula. 7-10 Drusen and basal deposits in aged eyes without ARM contain lipids, including cholesterol, 9 -13 and current evidence suggests that individual sub-RPE deposits are preferentially enriched in either neutral lipids or polar lipids. 13 The source of lipids and mechanisms of deposition are unknown. Analyses of BrM/ choroid lipid composition have implicated both local cells and plasma. 8,9 Atherosclerotic cardiovascular disease (CVD), the leading cause of death in Wester...

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“…Classically, these BM defects have been described as fragmentation or fracturing in association with calcification (81)(82)(83)(84)(85). Additional age-related changes in BM are typified by: 1) progressive thickening of the two collagenous layers; 2) modification and degeneration of collagen and elastin; 3) increased levels of advanced glycation end products, noncollagenous proteins and lipids; and 4) accumulation of several types of sub-RPE deposits (86)(87)(88)(89)(90)(91)(92)(93)(94)(95). It has also been suggested that the age-related abnormalities in BM eventually lead to photoreceptor degeneration as a result of increased hydrophobicity, reduced permeability, and impaired nutrient exchange between the choroid and the RPE.…”

Section: Morphological Correlates Of Early Amdmentioning

confidence: 99%

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

et al. 2006

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Today, the average life expectancy in developed nations is over 80 years and climbing. And yet, the quality of life during those additional years is often significantly diminished by the effects of age-related, degenerative diseases, including age-related macular degeneration (AMD), the leading cause of blindness in the elderly worldwide. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a highly specialized region of the ocular retina responsible for fine visual acuity. Estimates gathered from the most recent World Health Organization (WHO) global eye disease survey conservatively indicate that 14 million persons are blind or severely visually impaired because of AMD. The disease has a tremendous impact on the physical and mental health of the geriatric population and their families and is becoming a major public health burden.Currently, there is neither a cure nor a means to prevent AMD. Palliative treatment options for the less prevalent, late-stage 'wet' form of the disease include anti-neovascular agents, photodynamic therapy and thermal laser. There are no current therapies for the more common 'dry' AMD, except for the use of antioxidants that delay progression in 20%-25% of eyes. New discoveries, however, are beginning to provide a much clearer picture of the relevant cellular events, genetic factors, and biochemical processes associated with early AMD. Recently, compelling evidence has emerged that the innate immune system and, more specifically, uncontrolled regulation of the complement alternative pathway plays a central role in the pathobiology of AMD. The complement Factor H gene-which encodes the major inhibitor of the complement alternative pathway-is the first gene identified in multiple independent studies that confers a significant genetic risk for the development of AMD. The emergence of this new paradigm of AMD pathogenesis should hasten the development of novel diagnostic and therapeutic approaches for this disease that will dramatically improve the quality of our prolonged lifespan.

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Advanced Glycation End Products in Age-related Macular Degeneration

Cited by 172 publications

References 22 publications

The Role of Oxidative Stress in the Pathogenesis of Age-Related Macular Degeneration

The Role of Oxidative Stress in the Pathogenesis of Age-Related Macular Degeneration

Apolipoprotein B in Cholesterol-Containing Drusen and Basal Deposits of Human Eyes with Age-Related Maculopathy

Age‐related macular degeneration—emerging pathogenetic and therapeutic concepts

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