scholarly journals Inflammatory Mediators Induced by Amyloid-Beta in the Retina and RPE In Vivo: Implications for Inflammasome Activation in Age-Related Macular Degeneration

2013 ◽  
Vol 54 (3) ◽  
pp. 2225 ◽  
Author(s):  
Ruozhou Tom Liu ◽  
Jiangyuan Gao ◽  
Sijia Cao ◽  
Navroop Sandhu ◽  
Jing Z. Cui ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Amyloid Beta ◽  
Inflammatory Mediators ◽  
Age Related Macular Degeneration ◽  
Inflammasome Activation ◽  
Age Related

scholarly journals Differential Expression of Inflammasome-Related Genes in Induced Pluripotent Stem-Cell-Derived Retinal Pigment Epithelial Cells with or without History of Age-Related Macular Degeneration

2021 ◽  
Vol 22 (13) ◽  
pp. 6800
Author(s):  
Maria Hytti ◽  
Eveliina Korhonen ◽  
Heidi Hongisto ◽  
Kai Kaarniranta ◽  
Heli Skottman ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Retinal Pigment ◽  
Induced Pluripotent Stem Cell ◽  
Retinal Pigment Epithelial Cells ◽  
Age Related Macular Degeneration ◽  
Inflammasome Activation ◽  
Protein Clearance ◽  
Age Related ◽  
Induced Pluripotent ◽  
Pigment Epithelial Cells

Inflammation is a key underlying factor of age-related macular degeneration (AMD) and inflammasome activation has been linked to disease development. Induced pluripotent stem-cell-derived retinal pigment epithelial cells (iPSC-RPE) are an attractive novel model system that can help to further elucidate disease pathways of this complex disease. Here, we analyzed the effect of dysfunctional protein clearance on inflammation and inflammasome activation in iPSC-RPE cells generated from a patient suffering from age-related macular degeneration (AMD) and an age-matched control. We primed iPSC-RPE cells with IL-1α and then inhibited both proteasomal degradation and autophagic clearance using MG-132 and bafilomycin A1, respectively, causing inflammasome activation. Subsequently, we determined cell viability, analyzed the expression levels of inflammasome-related genes using a PCR array, and measured the levels of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and MCP-1 secreted into the medium. Cell treatments modified the expression of 48 inflammasome-related genes and increased the secretion of mature IL-1β, while reducing the levels of IL-6 and MCP-1. Interestingly, iPSC-RPE from an AMD donor secreted more IL-1β and expressed more Hsp90 prior to the inhibition of protein clearance, while MCP-1 and IL-6 were reduced at both protein and mRNA levels. Overall, our results suggest that cellular clearance mechanisms might already be dysfunctional, and the inflammasome activated, in cells with a disease origin.

scholarly journals Interactions between Apolipoprotein E Metabolism and Retinal Inflammation in Age-Related Macular Degeneration

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 635
Author(s):  
Monica L. Hu ◽  
Joel Quinn ◽  
Kanmin Xue
Keyword(s):  
Risk Factor ◽  
Apolipoprotein E ◽  
Macular Degeneration ◽  
Amyloid Beta ◽  
Complement System ◽  
Genetic Risk ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Retinal Inflammation ◽  
The Complement System

Age-related macular degeneration (AMD) is a multifactorial retinal disorder that is a major global cause of severe visual impairment. The development of an effective therapy to treat geographic atrophy, the predominant form of AMD, remains elusive due to the incomplete understanding of its pathogenesis. Central to AMD diagnosis and pathology are the hallmark lipid and proteinaceous deposits, drusen and reticular pseudodrusen, that accumulate in the subretinal pigment epithelium and subretinal spaces, respectively. Age-related changes and environmental stressors, such as smoking and a high-fat diet, are believed to interact with the many genetic risk variants that have been identified in several major biochemical pathways, including lipoprotein metabolism and the complement system. The APOE gene, encoding apolipoprotein E (APOE), is a major genetic risk factor for AMD, with the APOE2 allele conferring increased risk and APOE4 conferring reduced risk, in comparison to the wildtype APOE3. Paradoxically, APOE4 is the main genetic risk factor in Alzheimer's disease, a disease with features of neuroinflammation and amyloid-beta deposition in common with AMD. The potential interactions of APOE with the complement system and amyloid-beta are discussed here to shed light on their roles in AMD pathogenesis, including in drusen biogenesis, immune cell activation and recruitment, and retinal inflammation.

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

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.

scholarly journals Experimental Models in Neovascular Age Related Macular Degeneration

2020 ◽  
Vol 21 (13) ◽  
pp. 4627
Author(s):  
Olivia Rastoin ◽  
Gilles Pagès ◽  
Maeva Dufies
Keyword(s):  
Macular Degeneration ◽  
Experimental Models ◽  
Age Related Macular Degeneration ◽  
Vascular Endothelial ◽  
In Vivo Models ◽  
Age Related ◽  
Decoy Receptors ◽  
Endothelial Growth Factor

Neovascular age-related macular degeneration (vAMD), characterized by the neo-vascularization of the retro-foveolar choroid, leads to blindness within few years. This disease depends on angiogenesis mediated by the vascular endothelial growth factor A (VEGF) and to inflammation. The only available treatments consist of monthly intravitreal injections of antibodies directed against VEGF or VEGF/VEGFB/PlGF decoy receptors. Despite their relative efficacy, these drugs only delay progression to blindness and 30% of the patients are insensitive to these treatments. Hence, new therapeutic strategies are urgently needed. Experimental models of vAMD are essential to screen different innovative therapeutics. The currently used in vitro and in vivo models in ophthalmic translational research and their relevance are discussed in this review.

scholarly journals A Novel Complotype Combination Associates with Age-Related Macular Degeneration and High Complement Activation Levels in vivo

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Constantin C. Paun ◽  
Yara T. E. Lechanteur ◽  
Joannes M. M. Groenewoud ◽  
Lebriz Altay ◽  
Tina Schick ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Complement Activation ◽  
Age Related Macular Degeneration ◽  
Age Related

scholarly journals Age-Related Macular Degeneration Revisited: From Pathology and Cellular Stress to Potential Therapies

2021 ◽  
Vol 8 ◽  
Author(s):  
Majda Hadziahmetovic ◽  
Goldis Malek
Keyword(s):  
Macular Degeneration ◽  
Vision Loss ◽  
Clinical Care ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelial Cells ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
The Impact

Age-related macular degeneration (AMD) is a neurodegenerative disease of the aging retina, in which patients experience severe vision loss. Therapies available to patients are limited and are only effective in a sub-population of patients. Future comprehensive clinical care depends on identifying new therapeutic targets and adopting a multi-therapeutic approach. With this goal in mind, this review examines the fundamental concepts underlying the development and progression of AMD and re-evaluates the pathogenic pathways associated with the disease, focusing on the impact of injury at the cellular level, with the understanding that critical assessment of the literature may help pave the way to identifying disease-relevant targets. During this process, we elaborate on responses of AMD vulnerable cells, including photoreceptors, retinal pigment epithelial cells, microglia, and choroidal endothelial cells, based on in vitro and in vivo studies, to select stressful agents, and discuss current therapeutic developments in the field, targeting different aspects of AMD pathobiology.

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