AMD Genetics: Methods and Analyses for Association, Progression, and Prediction

Yan, Qi; Ding, Ying; Weeks, Daniel E.; Chen, Wei

doi:10.1007/978-3-030-66014-7_7

Cited by 9 publications

(7 citation statements)

References 59 publications

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“…A number of genetically-modified models for monogenic retinal degenerations may only represent part of the AMD phenotype [ 49 , 60 , 61 , 62 ]. The multifactorial nature of AMD complicates modeling its phenotype considerably [ 17 , 63 ]. Consequently, this lack of representative models severely hampers studies into the etiology and effective treatment modalities of the disease [ 17 , 44 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

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Sodium-Iodate Injection Can Replicate Retinal Degenerative Disease Stages in Pigmented Mice and Rats: Non-Invasive Follow-Up Using OCT and ERG

Koster

Hurk

Brink

et al. 2022

IJMS

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Purpose: The lack of suitable animal models for (dry) age-related macular degeneration (AMD) has hampered therapeutic research into the disease, so far. In this study, pigmented rats and mice were systematically injected with various doses of sodium iodate (SI). After injection, the retinal structure and visual function were non-invasively characterized over time to obtain in-depth data on the suitability of these models for studying experimental therapies for retinal degenerative diseases, such as dry AMD. Methods: SI was injected into the tail vein (i.v.) using a series of doses (0–70 mg/kg) in adolescent C57BL/6J mice and Brown Norway rats. The retinal structure and function were assessed non-invasively at baseline (day 1) and at several time points (1–3, 5, and 10-weeks) post-injection by scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), and electroretinography (ERG). Results: After the SI injection, retinal degeneration in mice and rats yielded similar results. The lowest dose (10 mg/kg) resulted in non-detectable structural or functional effects. An injection with 20 mg/kg SI did not result in an evident retinal degeneration as judged from the OCT data. In contrast, the ERG responses were temporarily decreased but returned to baseline within two-weeks. Higher doses (30, 40, 50, and 70 mg/kg) resulted in moderate to severe structural RPE and retinal injury and decreased the ERG amplitudes, indicating visual impairment in both mice and rat strains. Conclusions: After the SI injections, we observed dose-dependent structural and functional pathological effects on the retinal pigment epithelium (RPE) and retina in the pigmented mouse and rat strains that were used in this study. Similar effects were observed in both species. In particular, a dose of 30 mg/kg seems to be suitable for future studies on developing experimental therapies. These relatively easily induced non-inherited models may serve as useful tools for evaluating novel therapies for RPE-related retinal degenerations, such as AMD.

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Section: Discussionmentioning

confidence: 99%

“…The multifactorial nature of AMD complicates modeling its phenotype considerably [ 17 , 63 ]. Consequently, this lack of representative models severely hampers studies into the etiology and effective treatment modalities of the disease [ 17 , 44 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

Sodium-Iodate Injection Can Replicate Retinal Degenerative Disease Stages in Pigmented Mice and Rats: Non-Invasive Follow-Up Using OCT and ERG

Koster

Hurk

Brink

et al. 2022

IJMS

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“…Age-related macular degeneration (AMD) is a progressive vascular disease that mainly affects adults older than 55 years and causes severe and irreversible visual impairments, accounting for about 6-9% of blindness worldwide (1)(2)(3). Early-stage or dry AMD is the most common form, but the most severe form is neovascular or wet AMD-which accounts for 90% of AMD-related blindness (4). While dry AMD is characterized by the formation of drusen in the sub-retinal space, wet AMD is distinguished by the pathological growth of abnormal choroidal blood vessels known as choroidal neovascularization (CNV).…”

Section: Introductionmentioning

confidence: 99%

A novel optical imaging probe for targeted visualization of NLRP3 inflammasomes in a mouse model of age-related macular degeneration

2023

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PurposeWet form of age-related macular degeneration (wet AMD) is a progressive vascular disease that mainly affects older adults and causes severe and irreversible vision loss. A key complication of wet AMD is choroidal neovascularization (CNV), which may be driven in part by NLRP3 inflammasomes that are associated with macrophages migration to CNV lesions. Since activated NLRP3 is correlated with CNV, visualizing NLRP3 inflammasomes and their associated macrophages is of great interest to monitor wet AMD progression and develop effective therapies against it. However, to the best of our knowledge, current ophthalmic imaging systems do not permit such targeted imaging. Therefore, in this study, we developed InflammaProbe-1, an optical imaging probe for targeted visualization of NLRP3 inflammasomes in CNV lesions.MethodsInflammaProbe-1 was synthesized by conjugating a clinically relevant fluorophore, Oregon Green® 488, to the selective NLRP3 inhibitor, CY-09. The ability of InflammaProbe-1 to target NLRP3 was assessed with an enzyme-linked immunosorbent assay by comparing its ability to inhibit NLRP3-mediated secretion of IL-1β to that of CY-09 in LPS-primed and nigericin-stimulated BMDMs. In vitro confocal imaging of NLRP3 was performed on InflammaProbe-1-stained BMDMs that had been induced to express NLRP3 with LPS. In vivo imaging of NLRP3 was conducted on mouse laser induced choroidal neovascularization (LCNV), a model of AMD, 6 h after an intraperitoneal injection of InflammaProbe-1 at 10 mg/kg on day 4 post-LCNV.ResultsInflammaProbe-1 was just as effective as CY-09 at inhibiting IL-1β secretion (p < 0.01 at 10 μM for both the InflammaProbe-1 and CY-09 groups relative to the control). InflammaProbe-1-stained BMDMs that had been induced to express NLRP3 showed significantly brighter fluorescence than untreated cells (p < 0.0001 for LPS treatment group and p < 0.001 for LPS and nigericin treatment group). Furthermore, in vivo molecular imaging of NLRP3 was achieved in mouse LCNV.ConclusionWe propose that InflammaProbe-1 may be a useful molecular imaging probe to monitor the onset, progression, and therapeutic response of AMD and other NLRP3-mediated diseases.

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“…Aging-related disorders can be defined as the progressive occurrence of several defective cellular mechanisms or metabolic pathways, resulting in degeneration [ 1 ]. Age-related macular degeneration (AMD) is a neurodegenerative disease that is the leading cause of irreversible central vision loss among the elderly in developed countries [ 2 , 3 ]. AMD is the third leading cause of blindness globally, following cataracts and glaucoma [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Associations of Tumor Necrosis Factor-Alpha Gene Polymorphisms (TNF)-α TNF-863A/C (rs1800630), TNF-308A/G (rs1800629), TNF-238A/G (rs361525), and TNF-Alpha Serum Concentration with Age-Related Macular Degeneration

Zazeckyte

Gedvilaitė

Vilkeviciute

et al. 2022

Life

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Age-related macular degeneration (AMD) is a neurodegenerative disease leading to irreversible central vision loss among the elderly in developed countries. While the disease accounts for 9% of all cases of vision loss, the prevalence of AMD is likely to increase due to the exponential aging of the population. Due to this reason, our study aimed to determine the associations of tumor necrosis factor-alpha (TNF-α) gene single-nucleotide polymorphisms (SNPs) TNF-863A/C (rs1800630), TNF-308A/G (rs1800629), TNF-238A/G (rs361525), and TNF-α serum concentration with age-related macular degeneration. Analysis of TNF-α rs1800630, rs1800629, and rs361525 polymorphisms showed that the TNF-α rs1800630 A allele was statistically significantly more frequent in the exudative AMD group compared to the control group (p = 0.029). Additionally, the TNF-α rs1800630 A allele was more frequent in females with exudative AMD than in the control group of healthy females (p = 0.027). The TNF-α rs1800630 A allele was more frequent in females with exudative AMD than in females with early AMD (p = 0.014). TNF-α rs1800630, rs1800629, and rs361525 haplotype A-A-G were associated with decreased odds of exudative AMD (p < 0.0001), and haplotype A-G-G was associated with 24-fold increased exudative AMD occurrence (p < 0.0001). TNF-α protein levels were lower in subjects with exudative AMD compared to the control group (p < 0.001). The study showed significant associations between inflammatory cytokine TNF-α single-nucleotide polymorphisms and serum level with AMD pathogenesis. Analysis of TNF-α genotypes and serum concentration may be helpful for the AMD diagnosis.

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AMD Genetics: Methods and Analyses for Association, Progression, and Prediction

Cited by 9 publications

References 59 publications

Sodium-Iodate Injection Can Replicate Retinal Degenerative Disease Stages in Pigmented Mice and Rats: Non-Invasive Follow-Up Using OCT and ERG

Sodium-Iodate Injection Can Replicate Retinal Degenerative Disease Stages in Pigmented Mice and Rats: Non-Invasive Follow-Up Using OCT and ERG

A novel optical imaging probe for targeted visualization of NLRP3 inflammasomes in a mouse model of age-related macular degeneration

Associations of Tumor Necrosis Factor-Alpha Gene Polymorphisms (TNF)-α TNF-863A/C (rs1800630), TNF-308A/G (rs1800629), TNF-238A/G (rs361525), and TNF-Alpha Serum Concentration with Age-Related Macular Degeneration

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