Factor In Age-related Macular Degeneration Research Articles

Interactions Between Amyloid-β (1-42) and Hydroxyapatite-Cholesterol Spherules Associated with Age-Related Macular Degeneration.

Drusen deposition on sub-retinal pigment epithelium is the causal factor for age-related macular degeneration for the old-aged individuals. These deposits contain hydroxyapatite-cholesterol spherules on which several proteins and lipids accumulate to cover the retina and choroid, causing blurred vision and blindness. Amyloid-β, the known culprit in Alzheimer's disease, is one among the few major proteins known to occur in these deposits. In the present article, we report preliminary analyses of interactions between amyloid-β and hydroxyapatite-cholesterol composites using Thioflavin-T binding kinetics, solid-state NMR and transmission electron microscopy (TEM). Thioflavin-T fluorescence kinetics shows that amyloid-β (1-42) aggregates only under certain conditions of concentration of cholesterol in the hydroxyapatite-cholesterol composites prepared by two different methods. These results were confirmed by 1D 13C CPMAS solid-state NMR. TEM imaging revealed that there is an exposure of the cholesterol surface in the composites prepared by sonication method. These imaging experiments explain the dependence of aggregation kinetics on the exposure and availability of cholesterol surface in the composites to a certain extent.

Global Incidence, Progression, and Risk Factors of Age-Related Macular Degeneration and Projection of Disease Statistics in 30 Years: A Modeling Study

Objective: Age-related macular degeneration(AMD) has become a major cause of visual impairment worldwide, especially in the elderly. Estimates of incidence, progression rates, and risk factors of AMD vary among studies, complicating the understanding of its epidemiology. Methods: For this systematic review and meta-analysis, literature published up to March 1, 2021, was searched in both English and Chinese databases. Hierarchical Bayesian approaches were used to estimate pooled incidence, progression, and 95% credible intervals (CrIs). Results: Thirty studies were included. The pooled annual early and late AMD incidence rates were 1.59 (95% CrI: 1.18–2.11) and 0.23 (95% CrI: 0.14–0.34) per 100 person-years, respectively. The annual progression rate of AMD was 5.5 (95% CrI: 2.3–8.8) per 100 person-years. Smoking was an independent risk factor for both early and late AMD, whereas age, high-density lipoprotein cholesterol, and alcohol consumption were risk factors for early AMD incidence only. The projected number of new cases of early and late AMD in 2050 would be 39.05 million (95% CrI: 23.12–63.57) and 6.41 million (95% CrI: 3.37–13.22), respectively. Conclusion: The prediction the number of new cases of AMD is not equal across the globe. Our findings indicate the need for more rigorous control and prevention measures in AMD focus on its risk factors for early intervention. The epidemiological estimates reported in this study could inform to identify effective strategies for preventing AMD worldwide.

Melatonin level as a risk factor for age-related macular degeneration

Background. The current trend towards an increase in age-related macular degeneration (AMD) incidence rate in the population, including the working-age population, with a possible loss of professional activity, indicates the need for early preclinical identification of risk groups, timely prevention and treatment. In the prevention and treatment of AMD, the prospect of using melatonin is being actively discussed.Aim: to analyze serum and tear fluid levels of melatonin in patients with AMD and study their correlation with risk factors.Materials and methods. In the course of the study, two groups were formed: the main group - patients with non-exudative AMD and senile cataract (n = 40) and the reference group - conditionally healthy patients without AMD and cataract (n = 20). Patients of both groups were surveyed to identify risk factors for AMD. The content of melatonin in blood serum and lacrimal fluid was determined by enzyme-linked immunosorbent assay using the Melatonin ELISA Kit (USA).Results. In the course of the study, it was found that the concentration of melatonin in blood serum and tear fluid in patients with AMD was significantly lower than in patients of the reference group (p <0.05). Serum and tear fluid melatonin levels depend on the following factors: age, body mass index (BMI), arterial hypertension, eye color, insomnia, and night work. It is possible that the local determination of melatonin in the lacrimal fluid can be a biomarker in the determination of ophthalmic pathological conditions.Conclusion. The obtained results can be used as recommendations for clarifying individual regimens for the use of melatonin, especially in the treatment of patients with AMD.

Chromosome 10q26–driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium

Genome-wide association studies have identified the chromosome 10q26 (Chr10) locus, which contains the age-related maculopathy susceptibility 2 (ARMS2) and high temperature requirement A serine peptidase 1 (HTRA1) genes, as the strongest genetic risk factor for age-related macular degeneration (AMD) [L.G. Fritsche et al., Annu. Rev. Genomics Hum. Genet. 15, 151-171, (2014)]. To date, it has been difficult to assign causality to any specific single nucleotide polymorphism (SNP), haplotype, or gene within this region because of high linkage disequilibrium among the disease-associated variants [J. Jakobsdottir et al. Am. J. Hum. Genet. 77, 389-407 (2005); A. Rivera et al. Hum. Mol. Genet. 14, 3227-3236 (2005)]. Here, we show that HTRA1 messenger RNA (mRNA) is reduced in retinal pigment epithelium (RPE) but not in neural retina or choroid tissues derived from human donors with homozygous risk at the 10q26 locus. This tissue-specific decrease is mediated by the presence of a noncoding, cis-regulatory element overlapping the ARMS2 intron, which contains a potential Lhx2 transcription factor binding site that is disrupted by risk variant rs36212733. HtrA1 protein increases with age in the RPE-Bruch's membrane (BM) interface in Chr10 nonrisk donors but fails to increase in donors with homozygous risk at the 10q26 locus. We propose that HtrA1, an extracellular chaperone and serine protease, functions to maintain the optimal integrity of the RPE-BM interface during the aging process and that reduced expression of HTRA1 mRNA and protein in Chr10 risk donors impairs this protective function, leading to increased risk of AMD pathogenesis. HtrA1 augmentation, not inhibition, in high-risk patients should be considered as a potential therapy for AMD.

Risk Factors for Age-related Macular Degeneration in Benin City, Southern Nigeria

Objectives: Various risk factors for age-related macular degeneration (ARMD) have been postulated and identified. This study seeks to identify risk factors for cases with ARMD in our environment and proffer appropriate recommendations on ways to reduce the risk of its development and progression. Methods: This was a case–control hospital-based study conducted in the out-patient eye clinic of the Department of Ophthalmology, University of Benin Teaching Hospital, Benin City, Nigeria. The cases were patients attending the eye clinic, with a diagnosis of ARMD and the controls were patients without a diagnosis of ARMD for a period of 7 months, all 50 years and above. Chi-squared and Fisher exact analyses were used to explore variables. Logistic regression (unadjusted and adjusted) were used to determine possible risk factors and their interactions. Results: A total of 240 respondents made of 120 cases and 120 controls participated in the study. A higher proportion of the respondents in both study groups was in the age group 60 to 69 years; cases 48 (40.0%) and controls 49 (40.8%) years. Adjusted odds ratio (OR) for risk factors for ARMD includes male sex [OR: 3.07; 95% confidence interval (CI): 0.92–10.23], those who resided in urban areas (OR: 3.08; 95% CI: 0.13–73.14), those who were employed (OR: 1.45; 95% CI: 0.46–4.54), alcohol use (OR: 1.86; 95% CI: 0.21–16.61), regular consumption of fast foods (OR: 1.43; 95% CI: 0.00–2355.87), obesity (OR: 1.39; 95% CI: 0.46–4.16), use of nontinted glasses (OR: 0.43; 95% CI: 0.14–1.35), and diabetes (OR: 1.31; 95% CI: 0.30–5.63). Conclusion: In this study, increasing age, the female gender, increasing body weight, and myopia were positively associated with ARMD. Tertiary education, weekly consumption of fruits, and the use of tinted spectacles were protective against ARMD. Identifying these risk factors in our environment will be a major step in planning health awareness programs geared toward management of progression of ARMD.

Meta-analysis of risk factors for age-related macular degeneration in China

Meta-analysis of risk factors for age-related macular degeneration in China

RNA-seq analysis of ageing human retinal pigment epithelium: Unexpected up-regulation of visual cycle gene transcription.

Ageing presents adverse effects on the retina and is the primary risk factor for age‐related macular degeneration (AMD). We report the first RNA‐seq analysis of age‐related transcriptional changes in the human retinal pigment epithelium (RPE), the primary site of AMD pathogenesis. Whole transcriptome sequencing of RPE from human donors ranging in age from 31 to 93 reveals that ageing is associated with increasing transcription of main RPE‐associated visual cycle genes (including LRAT, RPE65, RDH5, RDH10, RDH11; pathway enrichment BH‐adjusted P = 4.6 × 10−6). This positive correlation is replicated in an independent set of 28 donors and a microarray dataset of 50 donors previously published. LRAT expression is positively regulated by retinoid by‐products of the visual cycle (A2E and all‐trans‐retinal) involving modulation by retinoic acid receptor alpha transcription factor. The results substantiate a novel age‐related positive feedback mechanism between accumulation of retinoid by‐products in the RPE and the up‐regulation of visual cycle genes.

Analysis of association of risk factors for age-related macular degeneration.

To evaluate the significance of risk factors and analyze their interrelationship in developing age-related macular degeneration (AMD). This is a multicenter, cross-sectional study conducted in eight ophthalmology centers in Europe. The STARS (Simplified Thea AMD Risk-Assessment Scale) questionnaire was used to assess 12 risk factors grouped in four major categories. We used Welch's t-test/F ratios to determine statistically significant changes. The principal component analysis was done to investigate the association between risk factors. There were 3297 participants included in our data analysis. Nineteen percent of patients had a high risk of developing AMD, whilst 45.92% and 34.85% had moderate and small risk, respectively. Atherosclerosis appeared as the most relevant risk indicator for AMD development (Cohen's d = 0.861). Tukey's post hoc analysis of the smoking variable showed that ex-smokers (p < 0.001) have a significantly high risk of developing AMD. The Welch's t-test showed pseudophakic patients have a higher risk of developing AMD than phakic ones. Then, we conducted the principal component analysis, which revealed a significant connection between smoking and male gender and between smoking and atherosclerosis. Pseudophakic patients were generally older and had more often myocardial infarction as compared to phakic patients. We showed that higher BMI, history of arterial hypertension, hypercholesterolemia, and atherosclerosis tend to occur together as risk factors for AMD. Risk factors evaluated in our study should be considered for the development of AMD.

Analyses of Risk Factors of Age-related Macular Degeneration Using Routine Health Check-up Data

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Common Genes Involved in Autophagy, Cellular Senescence and the Inflammatory Response in AMD and Drug Discovery Identified via Biomedical Databases.

PurposeRetinal pigment epithelial cell autophagy dysfunction, cellular senescence, and the retinal inflammatory response are key pathogenic factors in age-related macular degeneration (AMD), which has been reviewed in our previously work in 2019. This study aims to identify genes collectively involved in these three biological processes and target drugs in AMD.MethodsThe pubmed2ensembl database was used to perform text mining. The GeneCodis database was applied to analyze gene ontology biological process and the KEGG pathway. The STRING database was used to analyze protein–protein interaction analysis and hub genes were identified by the Cytoscape software. The Drug Gene Interaction Database was used to perform drug–gene interactions.ResultsWe identified 62 genes collectively involved in AMD, autophagy, cellular senescence, and inflammatory response, 19 biological processes including 42 genes, 11 enriched KEGG pathways including 37 genes, and 12 hub genes step by step via the above biomedical databases. Finally, five hub genes (IL-6, VEGF-A, TP53, IL-1β, and transforming growth factor [TGF]-β1) and their specific interaction modes were identified, corresponding with 24 target drugs with therapeutic potential for AMD.ConclusionsIL-6, VEGF-A, TP53, IL-1β, and TGF-β1 are pivotal in autophagy, cellular senescence, and the inflammatory response in AMD, corresponding with 24 drugs with therapeutic potential for AMD, providing definite molecular mechanisms for further research and new possibilities for AMD treatment in the future.Translational RelevanceIL-6, VEGF-A, TP53, IL-1β, and TGF-β1 may be new targets for AMD gene therapy and drug development.

Thyroid Disease Is Associated with Higher Age-Related Macular Degeneration Risk: Results from a Meta-Analysis of Epidemiologic Studies

Background: Although epidemiologic studies have suggested that thyroid disease may be a risk factor for age-related macular degeneration (AMD), this finding is still controversial. Objectives: The aim of this meta-analysis was to investigate whether an association exists between thyroid disease and medication and AMD in epidemiologic studies. Methods: We searched PubMed, EMBASE, and Google Scholar from their inception to March 2020 for cross-sectional, case-control, and cohort studies that assessed thyroid function and AMD risk. Data from selected studies were extracted, and a meta-analysis was performed using fixed-effects or random-effects models. The statistical heterogeneity (I²) among studies and the possibility of publication bias were evaluated. If I² >50%, a significant heterogeneity existed among studies, and a random-effects model was used to calculate the pooled RR. Otherwise, a fixed-effects model was performed. Results: A total of 13 epidemiologic studies that consisted of 7 thyroid disease and 7 thyroid medication studies were included. Statistically significant heterogeneity was observed in the study results (I²_{thyroid disease} = 80.1%; I²_{thyroid medication} = 69.0%). A significant positive association was found between thyroid disease and AMD, with an overall relative risk (RR) of 1.25 (95% CI: 1.02, 1.54). However, there was no statistical association between thyroid medication and AMD risk (pooled RR 1.26 [95% CI: 0.92–1.72]). Egger’s test indicated that there was no significant publication bias for thyroid disease (p = 0.889) or thyroid medication (p = 0.226). Conclusions: Our findings indicate that thyroid disease is associated with higher AMD risk. Thyroid disease prevention strategies may have a significant effect on the prevention of AMD and warrant further evaluation.

Macular Pigment Optical Density and its Determinants among Adults: ACross-sectional Study

Introduction: Interplay exists between the risk factors of Age-related Macular Degeneration (AMD) and the factors influencing Macular Pigment Optical Density (MPOD) level. Early diagnosis and antioxidants supplementation is the only intervention which may possibly slow down the macular degeneration. Aim: To measure MPOD and study the possible risk factors associated with subnormal MPOD among adults patients attending Outpatient Department (OPD). Materials and Methods: A cross-sectional study was conducted among patients aged 20 years and above who visited Ophthalmology OPD in a tertiary care centre during the month of August (between 1st to 31st) 2018. Only those having Best-Corrected Visual Acuity (BCVA) better than 6/60 were enrolled for the study. MPOD was measured using a macular densitometer (Macular Matrics II, USA). Patients found to have subnormal MPOD further underwent Optical Coherence Tomography (OCT) and fundus. Fischer’s-exact and Chi-Square tests were applied wherever applicable; differences were considered to be statistically significant at p-value &lt;0.05. Results: A total of 82 patients participated in the present study. Total of 45.1% participants were found to have subnormal MPOD using macular densitometer. Prevalence was least among &lt;30 years of age (nil) and maximum after 50 years (58.8%) (p&lt;0.05). Trends revealed that subnormal MPOD was more frequent among smokers (p=0.13), vegetarians (p=0.38) and those who were malnourished (under or over weight) (p=0.15), though not found to be statistically significant.Non-modifiable risk factors, an inverse relationship was observed between age and MPOD levels. Conclusion: The study noted associations between subnormal MPOD and multiple risk factors, several of which are modifiable factors. These modifiable risk factors included smoking and malnourishment.

Protection against light-induced retinal degeneration via dual anti-inflammatory and anti-angiogenic functions of thrombospondin-1.

Retinal photodamage is a high-risk factor for age-related macular degeneration (AMD), the leading cause of irreversible blindness worldwide. However, both the pathogenesis and effective therapies for retinal photodamage are still unclear and debated. The anti-inflammatory effects of thrombospondin-1 on blue light-induced inflammation in ARPE-19 cells and in retinal inflammation were evaluated. Furthermore, the anti-angiogenic effects of thrombospondin-1 on human microvascular endothelial cells (hMEC-1 cells) and a laser-induced choroidal neovascularisation (CNV) mouse model were evaluated. in vitro experiments, including western blotting, immunocytochemistry, migration assays and tube formation assays, as well as in vivo experiments, including immunofluorescence, visual electrophysiology, spectral-domain optical coherence tomography, and fluorescein angiography, were employed to evaluate the anti-inflammatory and anti-angiogenic effects of thrombospondin-1. Specific effects of blue light-induced retinal inflammation and pathological angiogenesis were reflected by up-regulation of pro-inflammatory factors and activation of angiogenic responses, predominantly regulated by the NF-κB and VEGFR2 pathways respectively. During the blue light-induced pathological progress, THBS-1 derived from retinal pigment epithelium down-regulated proteomics and biological assays. Thrombospondin-1 treatment also suppressed inflammatory infiltration and neovascular leakage. The protective effect of Thrombospondin-1 was additionally demonstrated by a substantial rescue of visual function. Mechanistically, thrombospondin-1 reversed blue light-induced retinal inflammation and angiogenesis by blocking the activated NF-κB and VEGFR2 pathways, respectively. Thrombospondin-1, with dual anti-inflammatory and anti-neovascularisation properties, is a promising agent for protection against blue light-induced retinal damage and retinal degenerative disorders which are pathologically associated with inflammatory and angiogenic progress. This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.

Perfluorooctanoic acid in indoor particulate matter triggers oxidative stress and inflammation in corneal and retinal cells

To investigate the particle size distribution of particulate matter and the concentration of specific perfluorinated compounds in indoor dust samples from several locations. Then, we used cell-based assays to investigate the effect of perfluorinated compounds on human corneal epithelial (HCEpiC), endothelial cells (HCEC) and retinal pigment epithelial cells (RPE). Indoor dust samples were collected at five different locations and PM50–10, PM10–2.5, and PM2.5–1 were fractionized. The presence and levels of 8:2 fluorotelomer alcohol, 10:2 fluorotelomer alcohol, and perfluorooctanoic acid were detected by gas chromatography–mass spectrometry. The effect of perfluorooctanoic acid on the activation of reactive oxygen species, transepithelial resistance as well as the expression of interleukin (IL)-6 and IL-8 were determined. The basolateral media of human corneal epithelial or human corneal endothelial cells were used to treat human corneal endothelial or retinal pigment epithelial cells, respectively to indicate the potential of ocular surface inflammation may result in retinal inflammation. Among perfluorinated compounds, only perfluorooctanoic acid was detected in all indoor dust samples. Perfluorooctanoic acid had the highest concentration among all perfluorinated compounds in the samples. Exposure to perfluorooctanoic acid impaired tight junction sealing and increased the levels of reactive oxygen species in human corneal epithelial cells. In human corneal epithelial cells, secretion of IL-6 and IL-8 in both apical and basolateral media was promoted significantly by perfluorooctanoic acid treatment. Stimulation with the basolateral media from perfluorooctanoic acid-treated human corneal epithelial cells induced inflammation in human corneal endothelial cells. The treatment of retinal pigment epithelial cells with the basolateral media from stimulated human corneal endothelial cells also elicited the secretion of proinflammatory cytokines. The results indicate that perfluorooctanoic acid exposure impaired the tight junction of corneal cells and caused inflammatory reactions in the retina. Exposure of the cornea to perfluorooctanoic acid contained in particulate matter might induce oxidative stress and inflammation in the retina and represent a risk factor for age-related macular degeneration.

Association of Age-Related Macular Degeneration with Cardiovascular Diseases in Korean Adults: 2017 Korea National Health and Nutrition Examination Surveys

Purpose : This study was to investigate the risk factors of age-related macular degeneration according to cardiovascular diseases in Korean adults over 40 years of age. Methods : National Health and Nutrition Survey the 7th 2017 survey of Health Surveys and ophthalmology examination for subjects age-related macular degeneration related cardiovascular diseases, sex, age, body mass index, and sociological factors logistic regression analysis was performed by correcting household income, education, current smoking rate, and monthly drinking rate, and the significance level was less than 0.050. Results : The prevalence of age-related macular degeneration over the age of 40 was 7.23% for men and 7.94% for women. For age-related macular degeneration, age(OR=1.050, p＜0.001), sex(OR=0.693, p=0.024), stroke(OR=0.353, p=0.004), and myocardial infarction(OR=2.033, p=0.032) was significant. BMI(OR=1.008, p=0.626), household income(OR=1.000, p=0.296), education level (OR=0.927, p=0.181), smoking rate(OR=0.873, p=0.397), drinking rate(OR=0.922, p=0.489), hypertension( OR=0.981, p=0.872), and angina pectoris(OR=0.732, p=0.357) were not significant. Conclusion : After correcting sociological factors in the relationship between age-related macular degeneration and cardiovascular diseases, statistically significant relationships were identified with age, sex, stroke, and myocardial infarction.

Nutritional Supplements in the Prevention of Age-Related Retinal Pathology

Oxidative stress due to the imbalance in the production and detoxification of reactive oxygen species in antioxidant defence system of the body, as well as subsequent chronic inflammation, is believed to be associated with age-related eye diseases. Prevention of chronic degenerative diseases such as age-related macular degeneration (AMD) and primary open-angle glaucoma are of particular interest. In the last decade, tremendous success has been achieved in the treatment of age-related retinal pathology. However, these treatments are expensive and require frequent monitoring and, in some cases, injections, which place a huge burden on both the healthcare system and patients. Consequently, considerable interest remains in preventing or slowing the progression of these diseases. Epidemiological studies have shown that diet is a modifiable risk factor for AMD, and nutritional modification with food antioxidant supplements is a particularly attractive method of prevention because of its potential benefits and relatively low cost. A large number of experimental studies, including clinical studies in animals and humans, have provided supporting evidence that antioxidant food additives inhibit the oxidation of macromolecules, as well as an inflammatory response that occurs in the pathogenesis of involutional retinal pathology, which ultimately inhibits its development and progression. This review discusses the role of antioxidant dietary supplements in the prevention of age-related retinal pathology.

Dietary Lutein, Zeaxanthin and Omega-3- Essential Fatty Acid Intake and Risk of Age-Related Macular Degeneration in a Selected Australian Population

Abstract Objectives The aim of this study was to assess the dietary intakes of lutein, zeaxanthin (L + Z) and omega-3-essential fatty acid(EFA) among a selected population of Australian based adults and to examine the effect of specified risk factors for age-related macular degeneration(AMD) on those levels. Methods A cross-sectional study involving 70 adults aged 19–52 years was carried out. Demographic data were obtained using an online self-administered questionnaire while dietary intakes were estimated using USDA's 24 hours recall questionnaire, the Victorian Cancer Council(Australia) food frequency questionnaire and anthropometric characteristics were obtained using a body composition analyzer. Dietary intakes of lutein, zeaxanthin, omega-3-EFA and anthropometric indices against the risk of AMD were established using descriptive statistics and Spearman correlation. Results The mean age of the population was 29.9 ± 8.1years with 51% men and 49% women. Women had a higher intake of L + Z (1908.6 μg/day versus 1032.8 μg/day) and alpha-linolenic acid(ALA) compared to men(1.7 ± 1.1 g/day versus 1.6 ± 1.2 g/day). Men consumed more omega-3-EFA than women (433 ± 397.1 mg/day versus 365 ± 210.7 mg/day). L + Z levels were higher among people of Middle Eastern and South Asian origin (&amp;gt;4000 μg/day) in the 19–25years age group. People of Middle Eastern, South East Asian and South Asian had the highest intake of omega-3-EFA(&amp;gt;500 mg/day) at ages 19–25, 26–32 and 34–52years respectively. Women aged 34–52years with a family history of AMD had higher levels of L + Z(&amp;gt;2500 μg/day) while women aged 26–32years with a family history of AMD had higher levels of ALA(&amp;gt;3 g/day). Ethnicity and L + Z were correlated (P = −0.456, P &amp;lt; 0.02). Higher levels of intake of L + Z (&amp;gt;4000 μg/day) were seen in participants aged 34–52years with a 5–10years residence in Australia. Participants who had less than 5–10years of residency had higher levels of omega-3-EFA(&amp;gt;500 mg/day) for ages 26–32years while those aged 34–52years who had less than 5years of residency had higher ALA(&amp;gt;4 g/day). Conclusions Intake levels for L + Z vary significantly among participants. Culturally specific dietary habits could feasibly influence the levels of intake of L + Z. Intake levels of omega-3-EFA were met. This study provides detailed intake levels of L + Z and omega-3-EFA for the ‘at-risk’ AMD group. Funding Sources No funding source.

Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration.

Oxidative stress-induced damage to the retinal pigment epithelium (RPE) is considered to be a key factor in age-related macular degeneration (AMD) pathology. RPE cells are constantly exposed to oxidative stress that may lead to the accumulation of damaged cellular proteins, lipids, nucleic acids, and cellular organelles, including mitochondria. The ubiquitin-proteasome and the lysosomal/autophagy pathways are the two major proteolytic systems to remove damaged proteins and organelles. There is increasing evidence that proteostasis is disturbed in RPE as evidenced by lysosomal lipofuscin and extracellular drusen accumulation in AMD. Nuclear factor-erythroid 2-related factor-2 (NFE2L2) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) are master transcription factors in the regulation of antioxidant enzymes, clearance systems, and biogenesis of mitochondria. The precise cause of RPE degeneration and the onset and progression of AMD are not fully understood. However, mitochondria dysfunction, increased reactive oxygen species (ROS) production, and mitochondrial DNA (mtDNA) damage are observed together with increased protein aggregation and inflammation in AMD. In contrast, functional mitochondria prevent RPE cells damage and suppress inflammation. Here, we will discuss the role of mitochondria in RPE degeneration and AMD pathology focused on mtDNA damage and repair, autophagy/mitophagy signaling, and regulation of inflammation. Mitochondria are putative therapeutic targets to prevent or treat AMD.

Mechanisms of FH Protection Against Neovascular AMD.

A common allele (402H) of the complement factor H (FH) gene is the major risk factor for age-related macular degeneration (AMD), the leading cause of blindness in the elderly population. Development and progression of AMD involves vascular and inflammatory components partly by deregulation of the alternative pathway of the complement system (AP). The loss of central vision results from atrophy and/or from abnormal neovascularization arising from the choroid. The functional link between FH, the main inhibitor of AP, and choroidal neovascularization (CNV) in AMD remains unclear. In a murine model of CNV used as a model for neovascular AMD (nAMD), intraocular human recombinant FH (recFH) reduced CNV as efficiently as currently used anti-VEGF (vascular endothelial growth factor) antibody, decreasing deposition of C3 cleavage fragments, membrane attack complex (MAC), and microglia/macrophage recruitment markers in the CNV lesion site. In sharp contrast, recFH carrying the H402 risk variant had no effect on CNV indicating a causal link to disease etiology. Only the recFH NTal region (recFH1-7), containing the CCPs1-4 C3-convertase inhibition domains and the CCP7 binding domain, exerted all differential biological effects. The CTal region (recFH7-20) containing the CCP7 and CCPs19-20 binding domains was antiangiogenic but did not reduce the microglia/macrophage recruitment. The antiangiogenic effect of both recFH1-20 and recFH-CCP7-20 resulted from thrombospondin-1 (TSP-1) upregulation independently of the C3 cleavage fragments generation. This study provides insight on the mechanistic role of FH in nAMD and invites to reconsider its therapeutic potential.

Resvega Alleviates Hydroquinone-Induced Oxidative Stress in ARPE-19 Cells.

Retinal pigment epithelial (RPE) cells maintain homeostasis at the retina and they are under continuous oxidative stress. Cigarette smoke is a prominent environmental risk factor for age-related macular degeneration (AMD), which further increases the oxidant load in retinal tissues. In this study, we measured oxidative stress and inflammatory markers upon cigarette smoke-derived hydroquinone exposure on human ARPE-19 cells. In addition, we studied the effects of commercial Resvega product on hydroquinone-induced oxidative stress. Previously, it was observed that Resvega induces autophagy during impaired protein clearance in ARPE-19 cells, for which it has the potential to alleviate pro-inflammatory pathways. Cell viability was determined while using the lactate dehydrogenase (LDH) and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, and the cytokine levels were measured using the enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) production were measured using the 2′,7′-dichlorofluorescin diacetate (H2DCFDA) probe. Hydroquinone compromised the cell viability and increased ROS production in ARPE-19 cells. Resvega significantly improved cell viability upon hydroquinone exposure and reduced the release of interleukin (IL)-8 and monocytic chemoattractant protein (MCP)-1 from RPE cells. Resvega, N-acetyl-cysteine (NAC) and aminopyrrolidine-2,4-dicarboxylic acid (APDC) alleviated hydroquinone-induced ROS production in RPE cells. Collectively, our results indicate that hydroquinone induces cytotoxicity and increases oxidative stress through NADPH oxidase activity in RPE cells, and resveratrol-containing Resvega products prevent those adverse effects.