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 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.

scholarly journals A Review of Completed and Ongoing Complement Inhibitor Trials for Geographic Atrophy Secondary to Age-Related Macular Degeneration

2021 ◽  
Vol 10 (12) ◽  
pp. 2580
Author(s):  
Omar A. Halawa ◽  
Jonathan B. Lin ◽  
Joan W. Miller ◽  
Demetrios G. Vavvas
Keyword(s):  
Macular Degeneration ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Western World ◽  
Complement Factor ◽  
Complement Protein ◽  
Pivotal Phase ◽  
Complement Inhibition ◽  
Exudative Amd ◽  
Age Related

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness among older adults in the Western world. While therapies exist for patients with exudative AMD, there are currently no approved therapies for non-exudative AMD and its advanced form of geographic atrophy (GA). The discovery of genetic variants in complement protein loci with increased susceptibility to AMD has led to the investigation of the role of complement inhibition in AMD with a focus on GA. Here, we review completed and ongoing clinical trials evaluating the safety and efficacy of these studies. Overall, complement inhibition in GA has yielded mixed results. The inhibition of complement factor D has failed pivotal phase 3 trials. Studies of C3 and C5 inhibition meeting their primary endpoint are limited by high rates of discontinuation and withdrawal in the treatment arm and higher risks of conversion to exudative AMD. Studies evaluating other complement members (CFB, CFH, CFI and inhibitors of membrane attack complex—CD59) are ongoing and could offer other viable strategies.

scholarly journals Outer retinal tubulation formation and clinical course of advanced age-related macular degeneration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alessandro Arrigo ◽  
Emanuela Aragona ◽  
Ottavia Battaglia ◽  
Andrea Saladino ◽  
Alessia Amato ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Müller Cells ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Advanced Age ◽  
Age Related ◽  
Dry Amd ◽  
Foveal Sparing ◽  
Wet Amd

AbstractOuter retinal tubulations (ORT) are a relatively new finding characterizing outer retinal atrophy. The main aim of the present study was to describe ORT development in advanced age-related macular degeneration (AMD) and to assess its relationship with disease’s severity. Patients with advanced AMD characterized either by macular neovascularization or geographic atrophy, showing signs of outer retinal disruption or retinal pigment epithelium atrophy on structural optical coherence tomography (OCT) at the inclusion examination were prospectively recruited. All the patients underwent complete ophthalmologic evaluation, structural OCT scans and fundus autofluorescence imaging. The planned follow-up was of 3-years. Main outcome measures were ORT prevalence, mechanism of ORT formation, mean time needed for complete ORT formation, best-corrected visual acuity (BCVA), definitely decreased autofluorescence (DDAF) area, questionably decreased autofluorescence (QDAF) area, retinal layer thickness, foveal sparing, number of intravitreal injections. We also assessed the possible role of external limiting membrane (ELM) and Müller cells in ORT pathogenesis. Seventy eyes (70 patients) were included; 43 showed dry AMD evolving to geographic atrophy, while 27 displayed the features of wet AMD. Baseline BCVA was 0.5 ± 0.5 LogMAR, decreasing to 0.9 ± 0.5 LogMAR at the 3-year follow-up (p < 0.01). We detected completely formed ORT in 26/70 eyes (37%), subdivided as follows: 20 eyes (77%) wet AMD and 6 eyes (23%) dry AMD (p < 0.01). ORT took 18 ± 8 months (range 3–35 months) to develop fully. We described the steps leading to ORT development, characterized by progressive involvement of, and damage to the photoreceptors, the ELM and the RPE. Eyes displaying ORT were associated with a smaller QDAF area, less retinal layers damage and lower rate of foveal sparing than eyes free of ORT (p < 0.01). We also described pigment accumulations simulating ORT, which were detected in 16/70 eyes (23%), associated with a greater loss of foveal sparing, increased DDAF area and smaller QDAF area at the 3-year follow-up (p < 0.01). In conclusion, this study provided a description of the steps leading to ORT development in AMD. ELM and Müller cells showed a role in ORT pathogenesis. Furthermore, we described a subtype of pigment hypertrophy mimicking ORT, evaluating its clinical utility.

Rapid Recurrence of Geographic Atrophy after Full Macular Translocation for Nonexudative Age-Related Macular Degeneration

Ophthalmology ◽  
2005 ◽  
Vol 112 (9) ◽  
pp. 1586-1591 ◽  
Author(s):  
Rahul N. Khurana ◽  
Gildo Y. Fujii ◽  
Alexander C. Walsh ◽  
Mark S. Humayun ◽  
Eugene de Juan ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Macular Translocation ◽  
Full Macular Translocation ◽  
Age Related
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