scholarly journals Epigenetic hallmarks of age-related macular degeneration are recapitulated in a photosensitive mouse model

2020 ◽  
Vol 29 (15) ◽  
pp. 2611-2624
Author(s):  
Jennings Luu ◽  
Les Kallestad ◽  
Thanh Hoang ◽  
Dominik Lewandowski ◽  
Zhiqian Dong ◽  
...  
Keyword(s):  
Mouse Model ◽  
Macular Degeneration ◽  
Acute Stress ◽  
The Elderly ◽  
Causal Link ◽  
Chromatin Accessibility ◽  
Age Related Macular Degeneration ◽  
Light Damage ◽  
Photoreceptor Degeneration ◽  
Age Related

Abstract Age-related macular degeneration (AMD) is a chronic, multifactorial disorder and a leading cause of blindness in the elderly. Characterized by progressive photoreceptor degeneration in the central retina, disease progression involves epigenetic changes in chromatin accessibility resulting from environmental exposures and chronic stress. Here, we report that a photosensitive mouse model of acute stress-induced photoreceptor degeneration recapitulates the epigenetic hallmarks of human AMD. Global epigenomic profiling was accomplished by employing an Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-Seq), which revealed an association between decreased chromatin accessibility and stress-induced photoreceptor cell death in our mouse model. The epigenomic changes induced by light damage include reduced euchromatin and increased heterochromatin abundance, resulting in transcriptional and translational dysregulation that ultimately drives photoreceptor apoptosis and an inflammatory reactive gliosis in the retina. Of particular interest, pharmacological inhibition of histone deacetylase 11 (HDAC11) and suppressor of variegation 3–9 homolog 2 (SUV39H2), key histone-modifying enzymes involved in promoting reduced chromatin accessibility, ameliorated light damage in our mouse model, supporting a causal link between decreased chromatin accessibility and photoreceptor degeneration, thereby elucidating a potential new therapeutic strategy to combat AMD.

scholarly journals TPC2 promotes choroidal angiogenesis and inflammation in a mouse model of neovascular age-related macular degeneration

2021 ◽  
Vol 4 (8) ◽  
pp. e202101047
Author(s):  
Yanfen Li ◽  
Christian Schön ◽  
Cheng-Chang Chen ◽  
Zhuo Yang ◽  
Raffael Liegl ◽  
...  
Keyword(s):  
Mouse Model ◽  
Macular Degeneration ◽  
Choroidal Neovascularization ◽  
Immune Activation ◽  
The Elderly ◽  
Age Related Macular Degeneration ◽  
Strong Immune Response ◽  
Age Related ◽  
Key Factor ◽  
Photoreceptor Death

Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly and can be classified either as dry or as neovascular (or wet). Neovascular AMD is characterized by a strong immune response and the inadequate release of cytokines triggering angiogenesis and induction of photoreceptor death. The pathomechanisms of AMD are only partly understood. Here, we identify the endolysosomal two-pore cation channel TPC2 as a key factor of neovascularization and immune activation in the laser-induced choroidal neovascularization (CNV) mouse model of AMD. Block of TPC2 reduced retinal VEGFA and IL-1β levels and diminished neovascularization and immune activation. Mechanistically, TPC2 mediates cationic currents in endolysosomal organelles of immune cells and lack of TPC2 leads to reduced IL-1β levels in areas of choroidal neovascularization due to endolysosomal trapping. Taken together, our study identifies TPC2 as a promising novel therapeutic target for the treatment of AMD.

scholarly journals A widespread decrease of chromatin accessibility in age-related macular degeneration

2018 ◽  
Author(s):  
Jie Wang ◽  
Cristina Zibetti ◽  
Peng Shang ◽  
Srinivasa R. Sripathi ◽  
Pingwu Zhang ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Advanced Disease ◽  
The Elderly ◽  
Chromatin Accessibility ◽  
Age Related Macular Degeneration ◽  
Epigenetic Changes ◽  
Altered Expression ◽  
Rpe Cells ◽  
Age Related ◽  
Pigmented Epithelium

AbstractAge-related macular degeneration (AMD) is a leading cause of blindness in the elderly. The extent to which epigenetic changes regulate AMD progression is unclear. Here we globally profiled chromatin accessibility in the retina and retinal pigmented epithelium (RPE) from AMD patients and controls. Global decreases in chromatin accessibility occurr in RPE in early AMD, and in the retina with advanced disease, suggesting that dysfunction in RPE cells drives disease progression. Footprints of photoreceptor and RPE-specific transcription factors are enriched in differentially accessible regions (DARs). Genes associated with DARs show altered expression in AMD. Cigarette smoke treatment of RPE cells recapitulates epigenomic changes seen in AMD, providing an epigenetic link between the known risk factors for AMD and AMD pathology. Finally, overexpression of HDAC11 is partially responsible for the reduction in chromatin accessibility, identifying potential new targets for treatment of AMD.

scholarly journals Impact of neovascular age-related macular degeneration: burden of patients receiving therapies in Japan

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shigeru Honda ◽  
Yasuo Yanagi ◽  
Hideki Koizumi ◽  
Yirong Chen ◽  
Satoru Tanaka ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Productivity Loss ◽  
Work Productivity ◽  
The Elderly ◽  
Developed Countries ◽  
Age Related Macular Degeneration ◽  
Resource Utilisation ◽  
Total Work ◽  
Healthcare Resource Utilisation ◽  
Age Related

AbstractThe chronic eye disorder, neovascular age-related macular degeneration (nAMD), is a common cause of permanent vision impairment and blindness among the elderly in developed countries, including Japan. This study aimed to investigate the disease burden of nAMD patients under treatment, using data from the Japan National Health and Wellness surveys 2009–2014. Out of 147,272 respondents, 100 nAMD patients reported currently receiving treatment. Controls without nAMD were selected by 1:4 propensity score matching. Healthcare Resource Utilisation (HRU), Health-Related Quality of Life (HRQoL), and work productivity loss were compared between the groups. Regarding HRU, nAMD patients had significantly increased number of visits to any healthcare provider (HCP) (13.8 vs. 8.2), ophthalmologist (5.6 vs. 0.8), and other HCP (9.5 vs. 7.1) compared to controls after adjusting for confounding factors. Additionally, nAMD patients had reduced HRQoL and work productivity, i.e., reduced physical component summary (PCS) score (46.3 vs. 47.9), increased absenteeism (18.14% vs. 0.24%), presenteeism (23.89% vs. 12.44%), and total work productivity impairment (33.57% vs. 16.24%). The increased number of ophthalmologist visits were associated with decreased PCS score, increased presenteeism and total work productivity impairment. The current study highlighted substantial burden for nAMD patients, requiring further attention for future healthcare planning and treatment development.

scholarly journals Neovascular Macular Degeneration: A Review of Etiology, Risk Factors, and Recent Advances in Research and Therapy

2021 ◽  
Vol 22 (3) ◽  
pp. 1170
Author(s):  
Arunbalaji Pugazhendhi ◽  
Margaret Hubbell ◽  
Pooja Jairam ◽  
Balamurali Ambati
Keyword(s):  
Risk Factors ◽  
Macular Degeneration ◽  
Kinase Inhibitors ◽  
Rho Kinase ◽  
The Elderly ◽  
Age Related Macular Degeneration ◽  
Gene Therapies ◽  
Rho Kinase Inhibitors ◽  
Age Related ◽  
Endothelial Growth Factor

Neovascular age-related macular degeneration (exudative or wet AMD) is a prevalent, progressive retinal degenerative macular disease that is characterized by neovascularization of the choroid, mainly affecting the elderly population causing gradual vision impairment. Risk factors such as age, race, genetics, iris color, smoking, drinking, BMI, and diet all play a part in nvAMD’s progression, with anti-vascular endothelial growth factor (anti-VEGF) therapy being the mainstay of treatment. Current therapeutic advancements slow the progression of the disease but do not cure or reverse its course. Newer therapies such as gene therapies, Rho-kinase inhibitors, and levodopa offer potential new targets for treatment.

scholarly journals Oxidative Stress and Mitochondrial Damage in Dry Age-Related Macular Degeneration Like NFE2L2/PGC-1α -/- Mouse Model Evoke Complement Component C5a Independent of C3

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 622
Author(s):  
Iswariyaraja Sridevi Gurubaran ◽  
Hanna Heloterä ◽  
Stephen Marry ◽  
Ali Koskela ◽  
Juha M. T. Hyttinen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mouse Model ◽  
Macular Degeneration ◽  
Complement Component ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Related Factor ◽  
Complement Factor ◽  
Age Related ◽  
Dry Amd

Aging-associated chronic oxidative stress and inflammation are known to be involved in various diseases, e.g., age-related macular degeneration (AMD). Previously, we reported the presence of dry AMD-like signs, such as elevated oxidative stress, dysfunctional mitophagy and the accumulation of detrimental oxidized materials in the retinal pigment epithelial (RPE) cells of nuclear factor erythroid 2-related factor 2, and a peroxisome proliferator-activated receptor gamma coactivator 1-alpha (NFE2L2/PGC1α) double knockout (dKO) mouse model. Here, we investigated the dynamics of inflammatory markers in one-year-old NFE2L2/PGC1α dKO mice. Immunohistochemical analysis revealed an increase in levels of Toll-like receptors 3 and 9, while those of NOD-like receptor 3 were decreased in NFE2L2/PGC1α dKO retinal specimens as compared to wild type animals. Further analysis showed a trend towards an increase in complement component C5a independent of component C3, observed to be tightly regulated by complement factor H. Interestingly, we found that thrombin, a serine protease enzyme, was involved in enhancing the terminal pathway producing C5a, independent of C3. We also detected an increase in primary acute phase C-reactive protein and receptor for advanced glycation end products in NFE2L2/PGC1α dKO retina. Our main data show C5 and thrombin upregulation together with decreased C3 levels in this dry AMD-like model. In general, the retina strives to mount an orchestrated inflammatory response while attempting to maintain tissue homeostasis and resolve inflammation.

scholarly journals Introduction to the multi-author review on macular degeneration

2020 ◽  
Vol 77 (5) ◽  
pp. 779-780 ◽  
Author(s):  
Anu Kauppinen
Keyword(s):  
Macular Degeneration ◽  
Vision Loss ◽  
The Elderly ◽  
Developed Countries ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Severe Vision Loss ◽  
Author Review ◽  
Dry Amd ◽  
Endothelial Growth Factor

AbstractProlonged life expectancies contribute to the increasing prevalence of age-related macular degeneration (AMD) that is already the leading cause of severe vision loss among the elderly in developed countries. In dry AMD, the disease culminates into vast retinal atrophy, whereas the wet form is characterized by retinal edema and sudden vision loss due to neovascularization originating from the choroid beneath the Bruch’s membrane. There is no treatment for dry AMD and despite intravitreal injections of anti-vascular endothelial growth factor (VEGF) that suppress the neovessel formation, also wet AMD needs new therapies to prevent the disease progression and to serve patients lacking of positive response to current medicines. Knowledge on disease mechanisms is a prerequisite for the drug development, which is hindered by the multifactorial nature of AMD. Numerous distinguished publications have revealed AMD mechanisms at the cellular and molecular level and in this multi-author review, we take a bit broader look at the topic with some novel aspects.

scholarly journals Targeting lateral inhibition to improve vision following macular degeneration

2020 ◽  
Author(s):  
M Rizzi ◽  
K Powell ◽  
MR Robinson ◽  
T Matsuki ◽  
J Hoke ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Lateral Inhibition ◽  
Visual Function ◽  
Therapeutic Target ◽  
Age Related Macular Degeneration ◽  
Photoreceptor Degeneration ◽  
Specific Mechanism ◽  
Inhibitory Circuits ◽  
Age Related ◽  
Developed World

AbstractMacular degeneration is the leading cause of blindness in the developed world. Whilst most patients lose sight owing to atrophic changes, no treatments currently exist that improve the vision deficit due to atrophy. Here, we identify loss of lateral inhibition as a specific mechanism by which photoreceptor degeneration reduces visual function beyond the atrophic area. We find that this inhibition is adaptive, and that if modulated can improve visual function, making inhibitory circuits an unexpected therapeutic target for age related macular degeneration and related disorders.

AN AUTOMATED METHOD TO DETECT AGE-RELATED MACULAR DEGENERATION FROM OPTICAL COHERENCE TOMOGRAPHIC IMAGES

2021 ◽  
pp. 2150036
Author(s):  
Anju Thomas ◽  
P. M. Harikrishnan ◽  
Varun P. Gopi ◽  
P. Palanisamy
Keyword(s):  
Early Detection ◽  
Macular Degeneration ◽  
The Elderly ◽  
Age Related Macular Degeneration ◽  
Data Sets ◽  
Sigmoid Function ◽  
Data Set ◽  
Automated Method ◽  
Age Related ◽  
Sd Oct

Age-related macular degeneration (AMD) is an eye disease that affects the elderly. AMD’s prevalence is increasing as society’s population ages; thus, early detection is critical to prevent vision loss in the elderly. Arrangement of a comprehensive examination of the eye for AMD detection is a challenging task. This paper suggests a new poly scale and dual path (PSDP) convolutional neural network (CNN) architecture for early-stage AMD diagnosis automatically. The proposed PSDP architecture has nine convolutional layers to classify the input image as AMD or normal. A PSDP architecture is used to enhance classification efficiency due to the high variation in size and shape of perforation present in OCT images. The poly scale approach employs filters of various sizes to extract features from local regions more effectively. Simultaneously, the dual path architecture incorporates features extracted from different CNN layers to boost features in the global regions. The sigmoid function is used to classify images into binary categories. The Mendeley data set is used to train the proposed network and tested on Mendeley, Duke, SD-OCT Noor, and OCTID data sets. The testing accuracy of the network in Mendeley, Duke, SD-OCT Noor, and OCT-ID is 99.73%,96.66%,94.89%,99.61%, respectively. The comparison with alternative approaches showed that the proposed algorithm is efficient in detecting AMD. Despite having been trained on the Mendeley data set, the proposed model exhibited good detection accuracy when tested on other data sets. This shows that the suggested model can distinguish AMD/Normal images from various data sets. As compared to other methods, the findings show that the proposed algorithm is efficient at detecting AMD. Rapid eye scanning for early detection of AMD could be possible with the proposed architecture. The proposed CNN can be applied in real-time due to its lower complexity and less learnable parameters.

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