scholarly journals Altered photoreceptor metabolism in mouse causes late stage age-related macular degeneration-like pathologies

2020 ◽  
Vol 117 (23) ◽  
pp. 13094-13104 ◽  
Author(s):  
Shun-Yun Cheng ◽  
Joris Cipi ◽  
Shan Ma ◽  
Brian P. Hafler ◽  
Rahul N. Kanadia ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Mammalian Target Of Rapamycin ◽  
The Elderly ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Photoreceptor Outer Segment ◽  
Metabolic Adaptations ◽  
Age Related ◽  
Disease Stages

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. While the histopathology of the different disease stages is well characterized, the cause underlying the progression, from the early drusen stage to the advanced macular degeneration stage that leads to blindness, remains unknown. Here, we show that photoreceptors (PRs) of diseased individuals display increased expression of two key glycolytic genes, suggestive of a glucose shortage during disease. Mimicking aspects of this metabolic profile in PRs of wild-type mice by activation of the mammalian target of rapamycin complex 1 (mTORC1) caused early drusen-like pathologies, as well as advanced AMD-like pathologies. Mice with activated mTORC1 in PRs also displayed other early disease features, such as a delay in photoreceptor outer segment (POS) clearance and accumulation of lipofuscin in the retinal-pigmented epithelium (RPE) and of lipoproteins at the Bruch’s membrane (BrM), as well as changes in complement accumulation. Interestingly, formation of drusen-like deposits was dependent on activation of mTORC1 in cones. Both major types of advanced AMD pathologies, including geographic atrophy (GA) and neovascular pathologies, were also seen. Finally, activated mTORC1 in PRs resulted in a threefold reduction in di-docosahexaenoic acid (DHA)–containing phospholipid species. Feeding mice a DHA-enriched diet alleviated most pathologies. The data recapitulate many aspects of the human disease, suggesting that metabolic adaptations in photoreceptors could contribute to disease progression in AMD. Identifying the changes downstream of mTORC1 that lead to advanced pathologies in mouse might present new opportunities to study the role of PRs in AMD pathogenesis.

Non-Nutritional Medical Treatments in Dry-Form (Non-Neovascular) Age-Related Macular Degeneration

2017 ◽  
pp. 145-148
Keyword(s):  
Macular Degeneration ◽  
Vision Loss ◽  
The Elderly ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Medical Treatments ◽  
Age Related ◽  
Dry Amd ◽  
Disease Study ◽  
Developed World

Age-related macular degeneration (AMD) is the major cause of blindness for the elderly population in the developed world. Although vision loss is mainly due to the neovascular form, dry AMD remains a challenge for ophthalmologists because of the lack of effective therapies. The Age-Related Eye Disease Study (AREDS) demonstrated the protective effect of dietary supplementation of antioxidants to slow down the progression of dry AMD. On the other hand, there has been no proven drug treatment for dry AMD to date. This review is aimed to discuss recent non-nutritional treatments for dry AMD and geographic atrophy.

scholarly journals Repository of proposed pathways and protein–protein interaction networks in age-related macular degeneration

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Fran M. Pool ◽  
Christina Kiel ◽  
Luis Serrano ◽  
Philip J. Luthert
Keyword(s):  
Oxidative Stress ◽  
Macular Degeneration ◽  
Protein Interaction ◽  
Complex Disease ◽  
The Elderly ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Protein Protein Interaction ◽  
Ppi Networks ◽  
Age Related

AbstractAge-related macular degeneration (AMD) is one of the commonest causes of sight loss in the elderly population and to date there is no intervention that slows or prevents early AMD disease progressing to blinding neovascularization or geographic atrophy. AMD is a complex disease and factors proposed to contribute to the development and progression of disease include aging, genetics, epigenetics, oxidative stress, pro-inflammatory state, and life-style factors such as smoking, alcohol, and high fat diet. Here, we generate a knowledge repository of pathways and protein–protein interaction (PPI) networks likely to be implicated in AMD pathogenesis, such as complement activation, lipid trafficking and metabolism, vitamin A cycle, oxidative stress, proteostasis, bioenergetics, autophagy/mitophagy, extracellular matrix (ECM) turnover, and choroidal vascular dropout. Two disctinct clusters ermerged from the networks for parainflamation and ECM homeostasis, which may represent two different disease modules underlying AMD pathology. Our analyses also suggest that the disease manifests primarily in RPE/choroid and less in neural retina. The use of standardized syntax when generating maps of these biological processes (SBGN standard) and networks (PSI standard) enables visualization of complex information in graphical programs such as CellDesigner and Cytoscape and enhances reusability and extension of data. The ability to focus onto subnetworks, multiple visualizations and simulation options will enable the AMD research community to computationally model subnetworks or to test experimentally new hypotheses arising from connectivities in the AMD pathway map.

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

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
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.

scholarly journals HK2 Mediated Glycolytic Metabolism in Mouse Photoreceptors Is Not Required to Cause Late Stage Age-Related Macular Degeneration-Like Pathologies

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 871
Author(s):  
Shun-Yun Cheng ◽  
Anneliese Malachi ◽  
Joris Cipi ◽  
Shan Ma ◽  
Richard S. Brush ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Aerobic Glycolysis ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Metabolic Adaptations ◽  
Age Related ◽  
Altered Glucose ◽  
Complex Protein ◽  
Lactate Levels ◽  
Unclear Etiology

Age-related macular degeneration (AMD) is a multifactorial disease of unclear etiology. We previously proposed that metabolic adaptations in photoreceptors (PRs) play a role in disease progression. We mimicked these metabolic adaptations in mouse PRs through deletion of the tuberous sclerosis complex (TSC) protein TSC1. Here, we confirm our previous findings by deletion of the other complex protein, namely TSC2, in rod photoreceptors. Similar to deletion of Tsc1, mice with deletion of Tsc2 in rods develop AMD-like pathologies, including accumulation of apolipoproteins, migration of microglia, geographic atrophy, and neovascular pathologies. Subtle differences between the two mouse models, such as a significant increase in microglia activation with loss of Tsc2, were seen as well. To investigate the role of altered glucose metabolism in disease pathogenesis, we generated mice with simulation deletions of Tsc2 and hexokinase-2 (Hk2) in rods. Although retinal lactate levels returned to normal in mice with Tsc2-Hk2 deletion, AMD-like pathologies still developed. The data suggest that the metabolic adaptations in PRs that cause AMD-like pathologies are independent of HK2-mediated aerobic glycolysis.

scholarly journals Evidence-Based Practice and Trends in Visual Rehabilitation for Patients with Age-Related Macular Degeneration

2021 ◽  
Author(s):  
Luis Leal Vega ◽  
Irene Alcoceba Herrero ◽  
Adrián Martín Gutiérrez ◽  
Joaquín Herrera Medina ◽  
Natalia Martín Cruz ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
The Elderly ◽  
Developed Countries ◽  
Functional Independence ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Evidence Based ◽  
Visual Rehabilitation ◽  
Evidence Based Practices ◽  
Age Related

Age-related macular degeneration (AMD) is a common, chronic, and progressive eye disease that is considered the leading cause of visual loss among the elderly in developed countries. Advanced AMD, including choroidal neovascularization (CNV) or geographic atrophy (GA), is associated with substantial and progressive visual impairment that can lead to a significant reduction in functional independence and quality of life (QoL) for affected individuals, whose number is expected to increase in the coming years in line with population growth and ageing. In this context, while an important part of medical care is focused on preventing the progression of the disease, Visual Rehabilitation (VR) aims to address its consequences by providing these patients with a number of strategies to achieve their goals and participate autonomously, actively and productively in society. This chapter aims to provide an update on evidence-based practices in the field and how modern technologies play an important role in the development of new VR approaches.

scholarly journals The Controversial Role of TGF-β in Neovascular Age-Related Macular Degeneration Pathogenesis

2018 ◽  
Vol 19 (11) ◽  
pp. 3363 ◽  
Author(s):  
Gian Tosi ◽  
Maurizio Orlandini ◽  
Federico Galvagni
Keyword(s):  
Macular Degeneration ◽  
Visual Loss ◽  
The Elderly ◽  
Developed Countries ◽  
Age Related Macular Degeneration ◽  
Transforming Growth Factors ◽  
Severe Visual Loss ◽  
Age Related ◽  
Experimental Approaches

The multifunctional transforming growth factors-beta (TGF-βs) have been extensively studied regarding their role in the pathogenesis of neovascular age-related macular degeneration (nAMD), a major cause of severe visual loss in the elderly in developed countries. Despite this, their effect remains somewhat controversial. Indeed, both pro- and antiangiogenic activities have been suggested for TGF-β signaling in the development and progression of nAMD, and opposite therapies have been proposed targeting the inhibition or activation of the TGF-β pathway. The present article summarizes the current literature linking TGF-β and nAMD, and reviews experimental data supporting both pro- and antiangiogenic hypotheses, taking into account the limitations of the experimental approaches.

scholarly journals Present and Possible Therapies for Age-Related Macular Degeneration

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Muhammad Khan ◽  
Ketan Agarwal ◽  
Mohamed Loutfi ◽  
Ahmed Kamal
Keyword(s):  
Macular Degeneration ◽  
Elderly Population ◽  
Treatment Options ◽  
The Elderly ◽  
Age Related Macular Degeneration ◽  
Common Cause ◽  
Age Related ◽  
Progressive Disorder ◽  
Additional Role

Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly population worldwide and is defined as a chronic, progressive disorder characterized by changes occurring within the macula reflective of the ageing process. At present, the prevalence of AMD is currently rising and is estimated to increase by a third by 2020. Although our understanding of the several components underpinning the pathogenesis of this condition has increased significantly, the treatment options for this condition remain substantially limited. In this review, we outline the existing arsenal of therapies available for AMD and discuss the additional role of further novel therapies currently under investigation for this debilitating disease.

scholarly journals Systemic Side Effects and Geographic Atrophy after Anti-VEGF Treatment in Wet-Form (Neovascular) Age-Related Macular Degeneration

2017 ◽  
pp. 256-261
Keyword(s):  
Side Effects ◽  
Macular Degeneration ◽  
The Elderly ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Vascular Endothelial ◽  
Anti Vegf ◽  
Age Related ◽  
Systemic Side Effects ◽  
Endothelial Growth Factor

Neovascular (wet-form) age-related macular degeneration (nARMD) is one of the leading causes of serious loss of vision in the elderly population. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents are commonly used in the treatment of nARMD. Systemic side effects and geographic atrophy following intravitreal administration of anti-VEGF agents in nARMD are mentioned in this review.

scholarly journals The role of microbiome in age-related macular degeneration: A review of the literature

2021 ◽  
Author(s):  
Athanasios Zisimopoulos ◽  
Olga Klavdianou ◽  
Panagiotis Theodossiadis ◽  
Irini Chatziralli
Keyword(s):  
Macular Degeneration ◽  
Human Microbiome ◽  
The Elderly ◽  
Age Related Macular Degeneration ◽  
Current Evidence ◽  
Severe Visual Loss ◽  
Age Related ◽  
New Treatment ◽  
Functional Profiles

Background: Age-related macular degeneration (AMD) is a progressive, multifactorial, degenerative disease and the leading cause of severe visual loss in the elderly population. The exact pathogenesis of AMD remains elusive, being the combination of genetic, environmental, metabolic and functional processes. Better understanding of the disease’s pathophysiology leads to new treatment targets. Human microbiome seems to be a potential therapeutic pathway for AMD, as it has been recently proven to play a role in its pathogenesis. Summary: This review shed light into the association between microbiome and AMD. Key messages: The current evidence based on the existing literature shows that there are differences in taxonomical and functional profiles in human microbiome between patients with AMD and controls, suggesting that microbiome is implicated in AMD onset and progression, being a link between AMD and nutrition/diet. Additionally, specific bacterial classes have been proposed as potential biomarkers for AMD diagnosis. Further randomized clinical studies with large sample are needed to elucidate the role of microbiome in AMD and to draw more solid conclusions.

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