The complement system and age-related macular degeneration

Sivaprasad, Sobha; Chong, Victor

doi:10.1038/sj.eye.6702176

Cited by 55 publications

(39 citation statements)

References 38 publications

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“…Ocular Inflammation-It is believed that RPE cell debris (lipofuscin) serves as a chronic inflammatory stimulus for complement activation and a potential nucleation site for drusen formation (27)(28)(29). Thus at 12 months, we used quantitative RT-PCR to determine whether the decreased ocular lipofuscin in response to treatment altered the expression of inflammatory cytokines and chemokines as well as their receptors.…”

Section: Ocular A2e and Atr-dimer-we Raised Two Groups Of Abca4mentioning

confidence: 99%

C20-D3-vitamin A Slows Lipofuscin Accumulation and Electrophysiological Retinal Degeneration in a Mouse Model of Stargardt Disease

Kaufman

Zhang

et al. 2011

Journal of Biological Chemistry

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Autosomal recessive Stargardt disease (STGD1) is a macular dystrophy resulting from mutations in the ABCA4 (ABCR) gene. The age of onset of Stargardt disease is typically 10 -20 years of age and leads in almost all cases to blindness by age 50 (1, 2). A hallmark of the disease is premature lipofuscin accumulation in the retinal pigment epithelium (RPE) 2 of the eye. The RPE is critical for the neurosensory retina homeostasis; it acts as a transport exchange system with blood capillaries and is critical for regeneration and phagocytosis of photoreceptor outer segments. It is hypothesized that when RPE lipofuscin reaches a critical level, it contributes to a decline in cell function (3-8) resulting in the degeneration of the macular region of the neurosensory retina leading to loss of central vision (9 -11).The defective gene in Stargardt, ABCA4, encodes for an outer segment rim protein (RmP). The function of RmP is to transport the all-trans-retinaldehyde-phosphatidylethanolamine (retinaldehyde-PE) Schiff base from the luminal side of the disk membrane to the cytosolic face, where retinaldehyde can then be converted back to retinol (3). In the absence of its proper transporter, the retinaldehyde-PE conjugates may react to form vitamin A dimers (A2E and ATR-dimer among others), which are then deposited in the RPE after phagocytosis of the photoreceptors outer segments. Numerous studies have demonstrated the toxicity of vitamin A dimers to cultured RPE cells and they are hypothesized to play a key role in lipofuscin formation and subsequent retinal degeneration (12, 13). Nevertheless, the exact mechanisms that lead to lipofuscin accumulation or to vision loss as a result of the impaired transport of the retinaldehyde-PE conjugates remain unclear.In the accompanying article, we have shown that the ratedetermining step in vitamin A dimerization is the cleavage of a C20 carbon-hydrogen bond of the retinaldehyde-PE Schiff base (14). Replacing the C20 hydrogen atoms of vitamin A with deuterium atoms (i.e. C20-D 3 -vitamin A) makes this bond harder to cleave and impedes vitamin A dimerization (14). In this study we sought to determine whether retarding the intrinsic reactivity of vitamin A to dimerize could slow lipofuscin formation in the RPE and delay changes associated with human Stargardt disease. To accomplish this we raised ABCA4 Ϫ/Ϫ mutant albino mice (the mouse model of human Stargardt's disease) on diets containing either C20-D 3 -vitamin A (the treated group) or vitamin A at its natural isotopic abundance (the control group) and measured the concentration of vitamin A dimers, lipofuscin and other biological markers indicative of ocular health in both groups. Treated mice exhibited an 80% reduction in A2E, a 95% reduction in ATR dimer and a 70% decrease in fundus autofluorescence at three months of age. After six months, the treated group showed fewer lipofuscin granules as visualized qualitatively by electron microscopy, and at 12 months they showed improved eye function as measured by electroretinogram (ERG). ...

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Section: Ocular A2e and Atr-dimer-we Raised Two Groups Of Abca4mentioning

confidence: 99%

C20-D3-vitamin A Slows Lipofuscin Accumulation and Electrophysiological Retinal Degeneration in a Mouse Model of Stargardt Disease

Kaufman

Zhang

et al. 2011

Journal of Biological Chemistry

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“…There is a substantial body of evidence implicating complement in age-related macular degeneration (AMD) both in humans and in experimental animals (Sivaprasad and Chong, 2006). AMD is the major cause of irreversible central vision loss in the elderly world wide (Tezel et al, 2004).…”

Section: Complement and Age-related Macular Degenerationmentioning

confidence: 99%

The role of complement system in ocular diseases including uveitis and macular degeneration

Jha

Bora

2007

Molecular Immunology

108

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In the normal eye, the complement system is continuously activated at low levels and both membranebound and soluble intraocular complement regulatory proteins tightly regulate this spontaneous complement activation. This allows protection against pathogens without causing any damage to self-tissue and vision loss. The complement system and complement regulatory proteins control the intraocular inflammation in autoimmune uveitis and play an important role in the development of corneal inflammation, age-related macular degeneration and diabetic retinopathy. The evidence derived from both animal models and patient studies support the concept that complement inhibition is a relevant therapeutic target in the treatment of various ocular diseases. Currently, several clinical trials using complement inhibitors are going on. It is possible that, in the near future, complement inhibitors might be used as therapeutic agents in eye clinics.

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“…It is thought that for some reason in AMD patients, abnormal regulation of the complement cascade occurs at a local level within Bruch's membrane and adjacent retinal pigment epithelial cells resulting in uncontrolled compliment activation and consequent drusen formation. 25 Recent 26,27 Another study has shown that individuals homozygous for the risk alleles (representing a tyrosine-histidine change at amino acid 402) have a 7.4-fold increased likelihood of AMD. 28 These studies confirm an initial hypothesis, which established that chronic inflammation involving the complement pathway could contribute to disease progression.…”

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confidence: 99%

Age-related macular degeneration: a perspective on genetic studies

Patel

Adewoyin

Chong

2007

Eye

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Aim Age-related macular degeneration (AMD) is a common macular disease in the developed world and recent studies have shown that specific genes may be associated with it and may contribute to a higher risk of developing AMD. Objective Our objective was to review systematically recent publications related to the genetics of AMD and provide relevant information that would help both scientists and clinicians in advising patients.

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The complement system and age-related macular degeneration

Cited by 55 publications

References 38 publications

C20-D3-vitamin A Slows Lipofuscin Accumulation and Electrophysiological Retinal Degeneration in a Mouse Model of Stargardt Disease

C20-D3-vitamin A Slows Lipofuscin Accumulation and Electrophysiological Retinal Degeneration in a Mouse Model of Stargardt Disease

The role of complement system in ocular diseases including uveitis and macular degeneration

Age-related macular degeneration: a perspective on genetic studies

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