VEGF Rescues Cigarette Smoking–Induced Human RPE Cell Death by Increasing Autophagic Flux: Implications of the Role of Autophagy in Advanced Age-Related Macular Degeneration

This study aimed to evaluate the role of APOE polymorphisms (rs429358 and rs7412) in the risk of age-related macular degeneration in a sample of the Southeastern Brazilian population. Seven hundred and five unrelated individuals were analyzed, 334 with age-related macular degeneration (case group), and 371 without the disease (control group). In the case group, patients were further stratified according to disease phenotypes, divided into dry and wet age-related macular degeneration, and non-advanced and advanced age-related macular degeneration. APOE polymorphisms (rs429358 and rs7412) were evaluated through polymerase chain reaction and direct sequencing. In the comparison of cases vs. controls, none of the associations reached statistical significance, considering the Bonferroni-adjusted P-value, although there was a suggestive protection for the E3/E4 genotype (OR = 0.626; P-value = 0.037) and E4 carriers (OR = 0.6515; P-value = 0.047). Statistically significant protection for both the E3/E4 genotype and E4 carriers was observed in the comparisons: advanced age-related macular degeneration vs. controls (OR = 0.3665, P-value = 0.491 × 10−3 and OR = 0.4031, P-value = 0.814 × 10−3, respectively), advanced age-related macular degeneration vs. non-advanced age-related macular degeneration (OR = 0.2529, P-value = 0.659 × 10−4 and OR = 0.2692, P-value = 0.631 × 10−4, respectively). In the comparison of wet age-related macular degeneration vs. control, protection was statistically significant only for E3/E4 (OR = 0.4052, P-value = 0.001). None of the comparisons demonstrated any significant association for E2 genotypes or E2 carriers in age-related macular degeneration risk in this study. Findings suggest a protective role of the E4 haplotype in the APOE gene in the risk for advanced and wet forms of age-related macular degeneration, in a sample of the Brazilian population. To our knowledge, this is the first Brazilian study to show the association between APOE polymorphisms and age-related macular degeneration.

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Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice

Scientific Reports ◽

10.1038/s41598-021-89978-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Donita L. Garland ◽

Eric A. Pierce ◽

Rosario Fernandez-Godino

Keyword(s):

Macular Degeneration ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Deposit Formation ◽

Genetic Ablation ◽

Age Related ◽

Complement Dysregulation

AbstractThe complement system plays a role in the formation of sub-retinal pigment epithelial (RPE) deposits in early stages of age-related macular degeneration (AMD). But the specific mechanisms that connect complement activation and deposit formation in AMD patients are unknown, which limits the development of efficient therapies to reduce or stop disease progression. We have previously demonstrated that C3 blockage prevents the formation of sub-RPE deposits in a mouse model of EFEMP1-associated macular degeneration. In this study, we have used double mutant Efemp1R345W/R345W:C5-/- mice to investigate the role of C5 in the formation of sub-RPE deposits in vivo and in vitro. The data revealed that the genetic ablation of C5 does not eliminate the formation of sub-RPE deposits. Contrarily, the absence of C5 in RPE cultures promotes complement dysregulation that results in increased activation of C3, which likely contributes to deposit formation even in the absence of EFEMP1-R345W mutant protein. The results also suggest that genetic ablation of C5 alters the extracellular matrix turnover through an effect on matrix metalloproteinases in RPE cell cultures. These results confirm that C3 rather than C5 could be an effective therapeutic target to treat early AMD.

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Outer retinal tubulation formation and clinical course of advanced age-related macular degeneration

Scientific Reports ◽

10.1038/s41598-021-94310-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Alessandro Arrigo ◽

Emanuela Aragona ◽

Ottavia Battaglia ◽

Andrea Saladino ◽

Alessia Amato ◽

...

Keyword(s):

Macular Degeneration ◽

Müller Cells ◽

Geographic Atrophy ◽

Age Related Macular Degeneration ◽

Advanced Age ◽

Age Related ◽

Dry Amd ◽

Foveal Sparing ◽

Wet Amd

AbstractOuter retinal tubulations (ORT) are a relatively new finding characterizing outer retinal atrophy. The main aim of the present study was to describe ORT development in advanced age-related macular degeneration (AMD) and to assess its relationship with disease’s severity. Patients with advanced AMD characterized either by macular neovascularization or geographic atrophy, showing signs of outer retinal disruption or retinal pigment epithelium atrophy on structural optical coherence tomography (OCT) at the inclusion examination were prospectively recruited. All the patients underwent complete ophthalmologic evaluation, structural OCT scans and fundus autofluorescence imaging. The planned follow-up was of 3-years. Main outcome measures were ORT prevalence, mechanism of ORT formation, mean time needed for complete ORT formation, best-corrected visual acuity (BCVA), definitely decreased autofluorescence (DDAF) area, questionably decreased autofluorescence (QDAF) area, retinal layer thickness, foveal sparing, number of intravitreal injections. We also assessed the possible role of external limiting membrane (ELM) and Müller cells in ORT pathogenesis. Seventy eyes (70 patients) were included; 43 showed dry AMD evolving to geographic atrophy, while 27 displayed the features of wet AMD. Baseline BCVA was 0.5 ± 0.5 LogMAR, decreasing to 0.9 ± 0.5 LogMAR at the 3-year follow-up (p < 0.01). We detected completely formed ORT in 26/70 eyes (37%), subdivided as follows: 20 eyes (77%) wet AMD and 6 eyes (23%) dry AMD (p < 0.01). ORT took 18 ± 8 months (range 3–35 months) to develop fully. We described the steps leading to ORT development, characterized by progressive involvement of, and damage to the photoreceptors, the ELM and the RPE. Eyes displaying ORT were associated with a smaller QDAF area, less retinal layers damage and lower rate of foveal sparing than eyes free of ORT (p < 0.01). We also described pigment accumulations simulating ORT, which were detected in 16/70 eyes (23%), associated with a greater loss of foveal sparing, increased DDAF area and smaller QDAF area at the 3-year follow-up (p < 0.01). In conclusion, this study provided a description of the steps leading to ORT development in AMD. ELM and Müller cells showed a role in ORT pathogenesis. Furthermore, we described a subtype of pigment hypertrophy mimicking ORT, evaluating its clinical utility.

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Age-Related Macular Degeneration: Role of Oxidative Stress and Blood Vessels

International Journal of Molecular Sciences ◽

10.3390/ijms22031296 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1296

Author(s):

Yue Ruan ◽

Subao Jiang ◽

Adrian Gericke

Keyword(s):

Oxidative Stress ◽

Macular Degeneration ◽

Vascular Function ◽

Vascular Dysfunction ◽

Therapeutic Strategies ◽

Vision Impairment ◽

Age Related Macular Degeneration ◽

Oxygen Species ◽

Age Related

Age-related macular degeneration (AMD) is a common irreversible ocular disease characterized by vision impairment among older people. Many risk factors are related to AMD and interact with each other in its pathogenesis. Notably, oxidative stress and choroidal vascular dysfunction were suggested to be critically involved in AMD pathogenesis. In this review, we give an overview on the factors contributing to the pathophysiology of this multifactorial disease and discuss the role of reactive oxygen species and vascular function in more detail. Moreover, we give an overview on therapeutic strategies for patients suffering from AMD.

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The role of Aflibercept in the management of age-related macular degeneration

Expert Opinion on Biological Therapy ◽

10.1517/14712598.2016.1167182 ◽

2016 ◽

Vol 16 (5) ◽

pp. 699-709 ◽

Cited By ~ 6

Author(s):

Muhammad Hassan ◽

Rubbia Afridi ◽

Mohammad Ali Sadiq ◽

Mohamed Kamel Soliman ◽

Aniruddha Agarwal ◽

...

Keyword(s):

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Age Related

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Role of Factor H and Related Proteins in Regulating Complement Activation in the Macula, and Relevance to Age-Related Macular Degeneration

Journal of Clinical Medicine ◽

10.3390/jcm4010018 ◽

2014 ◽

Vol 4 (1) ◽

pp. 18-31 ◽

Cited By ~ 24

Author(s):

Simon Clark ◽

Paul Bishop

Keyword(s):

Macular Degeneration ◽

Complement Activation ◽

Factor H ◽

Age Related Macular Degeneration ◽

Age Related ◽

Related Proteins

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A Review of the Role of the Intestinal Microbiota in Age-Related Macular Degeneration

Journal of Clinical Medicine ◽

10.3390/jcm10102072 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2072

Author(s):

Phoebe Lin ◽

Scott M. McClintic ◽

Urooba Nadeem ◽

Dimitra Skondra

Keyword(s):

Macular Degeneration ◽

Intestinal Microbiota ◽

Retinal Disease ◽

Age Related Macular Degeneration ◽

Intestinal Microbiome ◽

Age Related ◽

Intestinal Dysbiosis ◽

Apo E ◽

Dry Amd

Blindness from age-related macular degeneration (AMD) is an escalating problem, yet AMD pathogenesis is incompletely understood and treatments are limited. The intestinal microbiota is highly influential in ocular and extraocular diseases with inflammatory components, such as AMD. This article reviews data supporting the role of the intestinal microbiota in AMD pathogenesis. Multiple groups have found an intestinal dysbiosis in advanced AMD. There is growing evidence that environmental factors associated with AMD progression potentially work through the intestinal microbiota. A high-fat diet in apo-E-/- mice exacerbated wet and dry AMD features, presumably through changes in the intestinal microbiome, though other independent mechanisms related to lipid metabolism are also likely at play. AREDS supplementation reversed some adverse intestinal microbial changes in AMD patients. Part of the mechanism of intestinal microbial effects on retinal disease progression is via microbiota-induced microglial activation. The microbiota are at the intersection of genetics and AMD. Higher genetic risk was associated with lower intestinal bacterial diversity in AMD. Microbiota-induced metabolite production and gene expression occur in pathways important in AMD pathogenesis. These studies suggest a crucial link between the intestinal microbiota and AMD pathogenesis, thus providing a novel potential therapeutic target. Thus, the need for large longitudinal studies in patients and germ-free or gnotobiotic animal models has never been more pressing.

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