Histology of neovascular myopic macular degeneration

AbstractTo assess the histological correlate of neovascular or exudative myopic macular degeneration (nMMD) in highly myopic human eyes, we examined histomorphometrically histologic sections of enucleated eyes of Caucasian patients. The study included 284 eyes (age: 61.9 ± 13.7 years; range: 24–89 years; axial length: 25.5 ± 3.1 mm; range: 20–37 mm). An nMMD was detected in 5 eyes (axial length: 29.6 ± 2.6 mm; range: 26.0–31.0 mm). All these eyes showed within or close to the nMMD a macular Bruch’s membrane (BM) defect, fibrous tissue with erythrocyte-filled blood vessels, and proliferations of irregularly pigmented and irregularly piled-up retinal pigment epithelium (RPE) cells each of which was connected with a curled-up, PAS (Periodic-Acid-Shiff)-positive membrane. The nMMD lesions were covered by proliferated RPE cells. RPE cells were not detected within the retina. In binary regression analysis, a higher nMMD prevalence was associated with a higher prevalence of macular BM defects (odds ratio: > 1000; P < 0.001), while the association with axial length was not significant (P = 0.43) in that model. After adjustment for the presence of macular BM defects, the nMMD prevalence was not associated with BM thickness (measured at the posterior pole, equator-posterior pole midpoint, equator and shortly posterior to the ora serrata) (P = 0.10; P = 0.87; P = 0.40; and P = 0.36, respectively), RPE cell layer thickness (P = 0.83; P = 0.79; P = 0.31; P = 0.38, resp.), RPE cell density (P = 0.56; P = 0.91; P = 0.47; P = 0.87, resp.), choriocapillaris thickness (P = 0.47; P = 0.93; P = 0.41; P = 0.75, resp.), and choriocapillaris density (P = 0.99; P = 0.94; P = 0.17; P = 0.97, resp.). The results suggest that nMMD is characterized by a fibrous pseudo-metaplasia of the RPE and is strongly associated with macular BM defects, without other detected histomorphometric differences in thickness or density of the RPE, BM, and choriocapillaris.

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Fallopia Japonica and Prunella Vulgaris Inhibit Myopia Progression by Suppressing Akt and NFκB Mediated Inflammatory Reactions

10.20944/preprints202107.0228.v1 ◽

2021 ◽

Author(s):

Chia-Hung Lin ◽

Chih-Sheng Chen ◽

Yao-Chien Wang ◽

En-Shyh Lin ◽

Ching-Yao Chang ◽

...

Keyword(s):

Transforming Growth Factor Beta ◽

Axial Length ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Retinal Pigment Epithelial Cell ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Myopia Progression ◽

Rpe Cells ◽

Expression Levels

The increased global incidence of myopia requires the establishment of therapeutic approaches. Previous studies have suggested that inflammation plays an important role in the development and progression of myopia. We used human retinal pigment epithelial cell to study the molecular mechanisms on how FJE and PVE lowering the inflammation of the eye. The effect of FJE and PVE in MFD induced hamster model and explore the role of inflammation cytokines in myopia. Expression levels of IL-6, IL-8, and TNF-α were upregulated in retinal pigment epithelium (RPE) cells treated with IL-6 and TNF-α. FJ extract (FJE) + PV extract (PVE) reduced IL-6, IL-8, and TNF-α expression in RPE cells. Furthermore, FJE and PVE inhibited inflammation by attenuating the phosphorylation of protein kinase B (AKT), and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) pathway. In addition, we report two resveratrol + ursolic acid compounds from FJ and PV and their inhibitory activities against IL-6, IL-8, and TNF-α expression levels in RPE cells treated with IL-6 and TNF-α. FJE, PVE, and FJE + PVE were applied to MFD hamsters and their axial length was measured after 21 days. The axial length showed statistically significant differences between phosphate-buffered saline- and FJE-, PVE-, and FJE + PVE-treated MFD eyes. FJE + PVE suppressed expressions of IL-6, IL-8, and TNF-α. They also inhibited myopia-related transforming growth factor-beta (TGF)-β1, matrix metalloproteinase (MMP)-2, and NF-κB expression while increasing type Ⅰ collagen expression. Overall, these results suggest that FJE + PVE may have a therapeutic effect on myopia and be used as a potential treatment option.

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NLRP3 Inflammasome: Activation and Regulation in Age-Related Macular Degeneration

Mediators of Inflammation ◽

10.1155/2015/690243 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 35

Author(s):

Jiangyuan Gao ◽

Ruozhou Tom Liu ◽

Sijia Cao ◽

Jing Z. Cui ◽

Aikun Wang ◽

...

Keyword(s):

Macular Degeneration ◽

Pigment Epithelium ◽

Retinal Pigment ◽

The Elderly ◽

Geographic Atrophy ◽

Age Related Macular Degeneration ◽

Inflammasome Activation ◽

Related Factors ◽

Rpe Cells ◽

Age Related

Age-related macular degeneration (AMD) is the leading cause of legal blindness in the elderly in industrialized countries. AMD is a multifactorial disease influenced by both genetic and environmental risk factors. Progression of AMD is characterized by an increase in the number and size of drusen, extracellular deposits, which accumulate between the retinal pigment epithelium (RPE) and Bruch’s membrane (BM) in outer retina. The major pathways associated with its pathogenesis include oxidative stress and inflammation in the early stages of AMD. Little is known about the interactions among these mechanisms that drive the transition from early to late stages of AMD, such as geographic atrophy (GA) or choroidal neovascularization (CNV). As part of the innate immune system, inflammasome activation has been identified in RPE cells and proposed to be a causal factor for RPE dysfunction and degeneration. Here, we will first review the classic model of inflammasome activation, then discuss the potentials of AMD-related factors to activate the inflammasome in both nonocular immune cells and RPE cells, and finally introduce several novel mechanisms for regulating the inflammasome activity.

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Role of FGF and Hyaluronan in Choroidal Neovascularization in Sorsby Fundus Dystrophy

Cells ◽

10.3390/cells9030608 ◽

2020 ◽

Vol 9 (3) ◽

pp. 608

Author(s):

Alyson Wolk ◽

Dilara Hatipoglu ◽

Alecia Cutler ◽

Mariya Ali ◽

Lestella Bell ◽

...

Keyword(s):

Macular Degeneration ◽

Choroidal Neovascularization ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Tissue Inhibitor Of Metalloproteinase ◽

Rpe Cells ◽

Age Related ◽

Sorsby's Fundus Dystrophy

Sorsby’s fundus dystrophy (SFD) is an inherited blinding disorder caused by mutations in the tissue inhibitor of metalloproteinase-3 (TIMP3) gene. The SFD pathology of macular degeneration with subretinal deposits and choroidal neovascularization (CNV) closely resembles that of the more common age-related macular degeneration (AMD). The objective of this study was to gain further insight into the molecular mechanism(s) by which mutant TIMP3 induces CNV. In this study we demonstrate that hyaluronan (HA), a large glycosaminoglycan, is elevated in the plasma and retinal pigment epithelium (RPE)/choroid of patients with AMD. Mice carrying the S179C-TIMP3 mutation also showed increased plasma levels of HA as well as accumulation of HA around the RPE in the retina. Human RPE cells expressing the S179C-TIMP3 mutation accumulated HA apically, intracellularly and basally when cultured long-term compared with cells expressing wildtype TIMP3. We recently reported that RPE cells carrying the S179C-TIMP3 mutation have the propensity to induce angiogenesis via basic fibroblast growth factor (FGF-2). We now demonstrate that FGF-2 induces accumulation of HA in RPE cells. These results suggest that the TIMP3-MMP-FGF-2-HA axis may have an important role in the pathogenesis of CNV in SFD and possibly AMD.

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Mitophagy in the Retinal Pigment Epithelium of Dry Age-Related Macular Degeneration Investigated in the NFE2L2/PGC-1α-/- Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms21061976 ◽

2020 ◽

Vol 21 (6) ◽

pp. 1976 ◽

Cited By ~ 6

Author(s):

Iswariyaraja Sridevi Gurubaran ◽

Johanna Viiri ◽

Ali Koskela ◽

Juha M.T. Hyttinen ◽

Jussi J. Paterno ◽

...

Keyword(s):

Oxidative Stress ◽

Mouse Model ◽

Macular Degeneration ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Retinal Pigment Epithelial Cells ◽

Age Related Macular Degeneration ◽

Double Knockout ◽

Rpe Cells ◽

Age Related

Increased oxidative stress and mitochondrial damage are observed in protein aggregation diseases, such as age-related macular degeneration (AMD). We have recently reported elevated levels of oxidative stress markers, damaged mitochondria, accumulating lysosomal lipofuscin and extracellular drusen-like structures in the retinal pigment epithelial cells (RPE) of the dry AMD-resembling NFE2L2/PGC1α double knockout (dKO) mouse model. Here, we provide evidence of a disturbance in the autolysosomal machinery handling mitochondrial clearance in the RPE cells of one-year-old NFE2L2/PGC1α-deficient mice. Confocal immunohistochemical analysis revealed an upregulation of autophagosome marker microtubule-associated proteins 1A/1B light chain 3B (LC3B) as well as numerous mitophagy markers, such as PTE-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase (PARKIN) together with damaged mitochondria. However, we detected no evidence of increased autolysosome formation in transmission electron micrographs or of colocalization of lysosomal marker LAMP2 (lysosome-associated membrane protein 2) and the mitochondrial marker ATP synthase β in confocal micrographs. Interestingly, we observed an upregulation of late autolysosomal fusion Ras-related protein (Rab7) in the perinuclear space of RPE cells together with autofluorescence aggregates. Our results reveal that there is at least a relative decrease of mitophagy in the RPE cells of NFE2L2/PGC1α dKO mice. This further supports the hypothesis that mitophagy is a putative therapy target in AMD-like pathology.

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Implication of N-methyl-D-aspartate receptor In Homocysteine Induced Age related Macular Degeneration

10.21203/rs.3.rs-481688/v1 ◽

2021 ◽

Author(s):

Yara A. Samra ◽

Dina Kira ◽

Pragya Rajpurohit ◽

Riyaz Mohamed ◽

Leah Owen ◽

...

Keyword(s):

Macular Degeneration ◽

Vision Loss ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Mice Model ◽

Rpe Cells ◽

Aspartate Receptor ◽

Age Related ◽

Retinal Structure

Abstract Background: Age related macular degeneration (AMD) is a leading cause of vision loss in old people. Elevated homocysteine (Hcy), known as Hyperhomocysteinemia (HHcy) was reported in association with AMD. We previously reported that HHcy induces AMD like features. The current study suggests activation of N-Methyl-D-aspartate receptor (NMDAR) in retinal pigment epithelium (RPE) cells as a mechanism for HHcy-induced AMD. Serum Hcy and cystathione-β-synthase enzyme (CBS) were assessed by ELISA in AMD patients. The involvement of NMDAR in Hcy’s induced AMD features were evaluated 1)-In-vitro using ARPE-19 cells, primary RPE isolated from mice model of HHcy (CBS) and mouse choroidal endothelial cells (MCEC). 2)-In-vivo using wild type mice and mice deficient in RPE cells NMDAR (NMDARR -/-) with/without intravitreal injection of Hcy. Expression of retinal isolectin-B4, Ki67, HIF-1α, VEGF, NMDAR1 and albumin were assessed by immunofluorescence (IF), Western blot (WB), Optical coherence tomography (OCT), and fluorescein angiography (FA) to evaluate retinal structure, fluorescein leakage and development of choroidal neovascularization (CNV) in living mice. Results: Serum of the neovascular AMD patients showed significant increase in Hcy and decrease in CBS levels. Moreover, Hcy significantly increased angiogenic markers; HIF-1α, VEGF and NMDAR in RPE cells and Ki67 in MCEC. Hcy-injected WT mice showed disrupted retinal morphology and development of CNV. Knocking down NMDAR in RPE improved retinal structure and CNV induction.Conclusion: Our findings underscore the potential role for NMDAR in RPE cells in mediating Hcy-induced features of AMD and CNV induction, thus NMDAR inhibition could provide a promising therapeutic target for AMD.

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Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration.

10.1101/2021.08.19.457044 ◽

2021 ◽

Author(s):

Anne Senabouth ◽

Maciej Daniszewski ◽

Grace Lidgerwood ◽

Helena Liang ◽

Damian Hernandez ◽

...

Keyword(s):

Retinal Pigment Epithelium ◽

Macular Degeneration ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Disease Status ◽

Geographic Atrophy ◽

Age Related Macular Degeneration ◽

Rpe Cells ◽

Age Related ◽

Mitochondrial Functions

Induced pluripotent stem cells generated from patients with geographic atrophy as well as healthy individuals were differentiated to retinal pigment epithelium (RPE) cells. By integrating transcriptional profiles of 127,659 RPE cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identified 439 expression Quantitative Trait (eQTL) loci in cis that were associated with disease status and specific to subpopulations of RPE cells. We identified loci linked to two genes with known associations with geographic atrophy - PILRB and PRPH2, in addition to 43 genes with significant genotype x disease interactions that are candidates for novel genetic associations for geographic atrophy. On a transcriptome-only level, we identified molecular pathways significantly upregulated in geographic atrophy-RPE including in extracellular cellular matrix reorganisation, neurodegeneration, and mitochondrial functions. We subsequently implemented a large-scale proteomics analysis, confirming modification in proteins associated with these pathways. We also identified six significant protein (p) QTL that regulate protein expression in the RPE cells and in geographic atrophy - two of which share variants with cis-eQTL. Transcriptome-wide association analysis identified genes at loci previously associated with age-related macular degeneration. Further analysis conditional on disease status, implicated statistically significant RPE-specific eQTL. This study uncovers important differences in RPE homeostasis associated with geographic atrophy.

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Nanoceria Particles Are an Eligible Candidate to Prevent Age-Related Macular Degeneration by Inhibiting Retinal Pigment Epithelium Cell Death and Autophagy Alterations

Cells ◽

10.3390/cells9071617 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1617 ◽

Cited By ~ 4

Author(s):

Annamaria Tisi ◽

Vincenzo Flati ◽

Simona Delle Monache ◽

Luca Lozzi ◽

Maurizio Passacantando ◽

...

Keyword(s):

Cell Death ◽

Retinal Pigment Epithelium ◽

Macular Degeneration ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Cellular Damage ◽

Mesenchymal Transition ◽

Rpe Cells ◽

Age Related

Retinal pigment epithelium (RPE) dysfunction and degeneration underlie the development of age-related macular degeneration (AMD), which is the leading cause of blindness worldwide. In this study, we investigated whether cerium oxide nanoparticles (CeO2-NPs or nanoceria), which are anti-oxidant agents with auto-regenerative properties, are able to preserve the RPE. On ARPE-19 cells, we found that CeO2-NPs promoted cell viability against H2O2–induced cellular damage. For the in vivo studies, we used a rat model of acute light damage (LD), which mimics many features of AMD. CeO2-NPs intravitreally injected three days before LD prevented RPE cell death and degeneration and nanoceria labelled with fluorescein were found localized in the cytoplasm of RPE cells. CeO2-NPs inhibited epithelial-mesenchymal transition of RPE cells and modulated autophagy by the down-regulation of LC3B-II and p62. Moreover, the treatment inhibited nuclear localization of LC3B. Taken together, our study demonstrates that CeO2-NPs represent an eligible candidate to counteract RPE degeneration and, therefore, a powerful therapy for AMD.

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Ex Vivo Hyperspectral Autofluorescence Imaging and Localization of Fluorophores in Human Eyes with Age-Related Macular Degeneration

Vision ◽

10.3390/vision2040038 ◽

2018 ◽

Vol 2 (4) ◽

pp. 38

Author(s):

Taariq Mohammed ◽

Yuehong Tong ◽

Julia Agee ◽

Nayanika Challa ◽

Rainer Heintzmann ◽

...

Keyword(s):

Macular Degeneration ◽

Ex Vivo ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Emission Spectra ◽

Age Related Macular Degeneration ◽

Autofluorescence Imaging ◽

Age Related ◽

Human Eyes ◽

Similar Peak

To characterize fluorophore signals from drusen and retinal pigment epithelium (RPE) and their changes in age related macular degeneration (AMD), the authors describe advances in ex vivo hyperspectral autofluorescence (AF) imaging of human eye tissue. Ten RPE flatmounts from eyes with AMD and 10 from eyes without AMD underwent 40× hyperspectral AF microscopic imaging. The number of excitation wavelengths tested was initially two (436 nm and 480 nm), then increased to three (436 nm, 480 nm, and 505 nm). Emission spectra were collected at 10 nm intervals from 420 nm to 720 nm. Non-negative matrix factorization (NMF) algorithms decomposed the hyperspectral images into individual emission spectra and their spatial abundances. These include three distinguishable spectra for RPE fluorophores (S1, S2, and S3) in both AMD and non-AMD eyes, a spectrum for drusen (SDr) only in AMD eyes, and a Bruch’s membrane spectrum that was detectable in normal eyes. Simultaneous analysis of datacubes excited atthree excitation wavelengths revealed more detailed spatial localization of the RPE spectra and SDr within drusen than exciting only at two wavelengths. Within AMD and non-AMD groups, two different NMF initialization methods were tested on each group and converged to qualitatively similar spectra. In AMD, the peaks of the SDr at ~510 nm (436 nm excitation) were particularly consistent. Between AMD and non-AMD groups, corresponding spectra in common, S1, S2, and S3, also had similar peak locations and shapes, but with some differences and further characterization warranted.

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