Molecular pathology of age-related macular degeneration

Ding, Xiaoyan; Patel, Mrinali; Chan, Chi‐Chao

doi:10.1016/j.preteyeres.2008.10.001

Cited by 510 publications

(436 citation statements)

References 198 publications

(244 reference statements)

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“…Moreover, infiltrating macrophages are thought to participate in the inflammation associated with retinal degeneration (56)(57)(58). Retinal macrophages Fig.…”

Section: Discussionmentioning

confidence: 99%

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

Maeda

Palczewska

Golczak³

et al. 2014

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

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Atrophic age-related and juvenile macular degeneration are especially devastating due to lack of an effective cure. Two retinal cell types, photoreceptor cells and the adjacent retinal pigmented epithelium (RPE), reportedly display the earliest pathological changes. Abca4 −/− Rdh8 −/− mice, which mimic many features of human retinal degeneration, allowed us to determine the sequence of light-induced events leading to retinal degeneration. Using two-photon microscopy with 3D reconstruction methodology, we observed an initial strong retinoid-derived fluorescence and expansion of Abca4 −/− Rdh8 −/− mouse rod cell outer segments accompanied by macrophage infiltration after brief exposure of the retina to bright light. Additionally, light-dependent fluorescent compounds produced in rod outer segments were not transferred to the RPE of mice genetically defective in RPE phagocytosis. Collectively, these findings suggest that for light-induced retinopathies in mice, rod photoreceptors are the primary site of toxic retinoid accumulation and degeneration, followed by secondary changes in the RPE.

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“…Moreover, infiltrating macrophages are thought to participate in the inflammation associated with retinal degeneration (56)(57)(58). Retinal macrophages Fig.…”

Section: Discussionmentioning

confidence: 99%

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

Maeda

Palczewska

Golczak³

et al. 2014

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

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“…[2][3][4][5][6] In addition to these factors, various single-nucleotide polymorphisms (SNPs) have been widely reported to be associated with AMD. 7 Genome-wide association studies (GWAS) have confirmed multiple AMD-associated loci on chromosomes 1 and 10, including the genes CFH, C2, C3, CFB, ARMS2, and HTRA1. Recently, a large-scale GWAS with thousands of cases and controls reported several additional AMD-associated loci, including rs9621532 near the tissue inhibitor of metalloproteinase 3 (TIMP3) and synapsin III (SYN3) region of chromosome 22q12.3.…”

Section: Introductionmentioning

confidence: 99%

Influence of TIMP3/SYN3 polymorphisms on the phenotypic presentation of age-related macular degeneration

et al. 2013

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Age-related macular degeneration (AMD) is a leading cause of irreversible central visual loss in the elderly. A recent genomewide association studies (GWAS) reported that rs9621532 near the tissue inhibitor of metalloproteinase 3 (TIMP3)/synapsin III (SYN3) region of 22q12.3 is associated with AMD. In this study, we characterize its phenotypic influence on AMD using three independent study cohorts: case-control studies from the National Eye Institute Clinical Center (NEI, n ¼ 397) and the AgeRelated Eye Disease Study (n ¼ 523) as well as a nested case-control study from Blue Mountains Eye Study (BMES, n ¼ 852).Comparisons between cases and controls show no association between rs9621532 and AMD in the three sample sets. However, stratifying NEI cases uncovers a moderate protective role of rs9621532 in neovascular AMD (nAMD) and the association adhered to a dominant model (odds ratios ¼ 0.32; 95% CI: 0.11-0.89; P ¼ 0.02). The BMES data followed the same pattern of association with nAMD as that seen in the NEI sample but did not reach statistical significance. Polychotomous logistic regression showed a trend that rs9621532 correlates with less severe disease, for example, with the majority of carriers having intermediate AMD rather than nAMD/geographic atrophy AMD. Functionally, rs9621532 influences TIMP3 mRNA expression in cultured primary human fetal retinal pigment epithelium (hfRPE) cells. In hfRPE donors carrying the protective rs9625132 allele, we measured a reduction in TIMP3 mRNA by quantitative RT-PCR. Our data suggest that rs9621532 carriers have a lower risk of developing nAMD, potentially because of decreased transcription of TIMP3.

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“…Decline in visual functions, particularly dark adaptation, becomes yet another potential biomarker in monitoring/predicting pathologies leading to AMD (22)(23)(24). Although development of a large number of animal models has helped to advance our understanding of retinal pathobiology and identify specific genetic factors that contribute to photoreceptor degeneration, inflammation, and the biochemistry of many retinal processes, these models all have limitations (25)(26)(27)(28). No one animal model fully recapitulates all the phenotypes of human retinal pathology, and patients with AMD also do not fully resemble each other.…”

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confidence: 99%

Serum levels of lipid metabolites in age‐related macular degeneration

et al. 2015

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Age-related macular degeneration (AMD) is a neurodegenerative disease that causes adult-onset blindness. There are 2 forms of this progressive disease: wet and dry. Currently there is no cure for AMD, but several treatment options have started to emerge making early detection critical for therapeutic success. Analysis of the eyes of Abca4 2/2 Rdh8 2/2 mice that display light-induced retinal degeneration indicates that 11-cis-retinal and docosahexaenoic acid (DHA) levels were significantly decreased as compared with the eyes of control dark-adapted C57BL/6J mice. In addition, exposure to intense light correlated with higher levels of prostaglandin G2 in the eyes of Abca4 2/2 Rdh8 2/2 mice. Intense light exposure also lowered DHA levels in the eyes of wild-type C57BL/6J mice without discernible retinal degeneration. Analysis of human serum from patients with AMD recapitulated these dysregulated DHA levels and revealed dysregulation of arachidonic acid (AA) levels as well (∼32% increase in patients with AMD compared with average levels in healthy individuals). From these observations, we then built a statistical model that included levels of DHA and AA from human serum. This model had a 74% probability of correctly identifying patients with AMD from controls. Addition of a genetic analysis for one of the most prevalent amino acid substitutions in the age-related maculopathy susceptibility 2 gene linked to AMD, Ala 69 →Ser, did not improve the statistical model. Thus, we have characterized a reliable method with the potential to detect AMD without a genetic component, paving the way for a larger-scale clinical evaluation. Our studies on mouse models along with the analysis of human serum suggest that our small molecule-based model may serve as an effective tool to estimate the risk of developing AMD.-Orban, T., Johnson, W. M., Dong, Z., Maeda, T., Maeda, A., Sakai, T., Tsuneoka, H., Mieyal, J. J., Palczewski, K. Serum levels of lipid metabolites in age-related macular degeneration. FASEB J. 29, 4579-4588 (2015). www.fasebj.org

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Molecular pathology of age-related macular degeneration

Cited by 510 publications

References 198 publications

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

Influence of TIMP3/SYN3 polymorphisms on the phenotypic presentation of age-related macular degeneration

Serum levels of lipid metabolites in age‐related macular degeneration

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