Molecular Mechanisms of Druze Formation in the Retina in Age-Related Macular Degeneration
https://doi.org/10.18008/1816-5095-2020-3S-550-555
Abstract
Age-related macular degeneration is the main cause of vision loss in aged people. A significant risk factor of disease is considered dysfunction of retinal pigment epithelium, which is accompanied by accumulation of lipids in Bruch membrane as drusen or linear deposits. As a result, there are disturbance of substances and oxygen transport from blood to retina cells of eye as well as elimination of toxic catabolites to choroid capillaries. The lack of a systematic analysis of pathogenetic mechanisms of drusen’s formation in age-related macular degeneration controls possibility of developing methods for treating and preventing development of early stage of age-related macular degeneration. There are the data of risk factors and pathogenesis of age-related macular degeneration in the article. It pays attention to the significance of oxidative stress in pigment epithelium of macula and triggering factors of inflammation development in eye retina. In context of differences in lipid composition and topographic location of cones and rods photoreceptor cells the localization of drusen, basal laminar and linear deposits in Bruch membrane is discussed. The possible mechanisms of drusen biogenesis associated with functioning of cholesterol carriers and lipid autophagy in retinal pigment epithelial cells as well as the role of macrophages in transport of local cholesterol depot to systemic circulation are presented. Analysis of literature allowed to identify several promising areas of development of targeted therapy for lipid metabolism disorders in retina. They include the reactivation of lipid carriers in RPE cells, ligand-receptor mechanisms that provide a reduction pH in lysosomes and maintaining functional activity of macrophages.
About the Author
E. F. Barinov
M. Gorky Donetsk State Medical University
Ukraine
Ukraine
MD, Professor, Head of the Histology, Cytology and Embryology Department
Il’icha ave., 16, Donetsk, 83003, Ukraine
References
1. Brandl C., Brücklmayer C., Günther F., Zimmermann M.E., Küchenhoff H., Helbig H., Weber B.H.F., Heid I.M., Stark K.J. Retinal Layer Thicknesses in Early Age‑Related Macular Degeneration: Results From the German AugUR Study. Invest Ophthalmol Vis Sci. 2019;60(5):1581–1594. DOI: 10.1167/iovs.18‑25332
2. Brown E.E., Ball J.D., Chen Z., Khurshid G.S., Prosperi M., Ash J.D. The Common Antidiabetic Drug Metformin Reduces Odds of Developing Age‑Related Macular Degeneration. Invest Ophthalmol Vis Sci. 20191;60(5):1470–1477. DOI: 10.1167/iovs.18‑26422
3. Jonasson F., Fisher D.E., Eiriksdottir G., Sigurdsson S., Klein R., Launer L.J., Harris T., Gudnason V., Cotch M.F. Five‑year incidence, progression, and risk factors for age‑related macular degeneration: the age, gene/environment susceptibility study. Ophthalmology. 2014;121:1766–1772. DOI: 10.1016/j.ophtha.2014.03.013
4. Handa J.T., Cano M., Wang L., Datta S., Liu T. Lipids, oxidized lipids, oxidation-specific epitopes, and Age‑related Macular Degeneration. Biochim Biophys Acta Mol Cell Biol Lipids. 2017;1862(4):430–440. DOI: 10.1016/j.bbalip.2016.07.013
5. Telegina D.V., Kozhevnikova O.S., Kolosova N.G. Changes in retinal glial cells with age and during development of age‑related macular degeneration. Biochemistry (Mosc). 2018;83(9):1009–1017. DOI: 10.1134/S000629791809002X
6. Kwon H.J., Lee S.M., Pak K.Y., Park S.W., Lee J.E., Byon I.S. Gender differences in the relationship between sex hormone deficiency and soft drusen. Curr Eye Res. 2017;42(11):1527–1536. DOI: 10.1080/02713683.2017.1337155
7. Colijn J.M., den Hollander A.I., Demirkan A., Cougnard‑Grégoire A., Verzijden T., Kersten E., Meester‑Smoor M.A., Merle B.M.J., Papageorgiou G., Ahmad S., Mulder M.T., Costa M.A., Benlian P., Bertelsen G., Bron A.M., Claes B., Creuzot‑Garcher C., Erke M.G., Fauser S., Foster P.J., Hammond C.J., Hense H.W., Hoyng C.B., Khawaja A.P., Korobelnik J.F., Piermarocchi S., Segato T., Silva R., Souied E.H., Williams K.M., van Duijn C.M., Delcourt C., Klaver C.C.W. Increased high‑density lipoprotein levels associated with age‑related macular degeneration: evidence from the eye‑risk and european eye epidemiology consortia. Ophthalmology. 2019;126(3):393–406.DOI: 1016/j.ophtha.2018.09.045
8. Oeverhaus M., Meyer Zu., Westrup V., Dietzel M., Hense H.W., Pauleikhoff D. Genetic polymorphisms and the phenotypic characterization of individuals with early Age‑Related Macular Degeneration. Ophthalmologica. 2017;238(1–2):6–16. DOI: 10.1159/000468949
9. Neale B.M., Fagerness J., Reynolds R., Sobrin L., Parker M., Raychaudhuri S., Tan P.L., Oh E.C., Merriam J.E., Souied E. Genome‑wide association study of advanced age‑related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc. Natl. Acad. Sci. USA. 2010;107:7395–7400. DOI: 10.1073/pnas.0912019107
10. Liutkeviciene R., Vilkeviciute A., Smalinskiene A., Tamosiunas A., Petkeviciene J., Zaliuniene D., Lesauskaite V. The role of apolipoprotein E (rs7412 and rs429358) in age‑related macular degeneration. Ophthalmic Genet. 2018;39(4):457–462. DOI: 10.1080/13816810.2018.1479429
11. Liutkevičienė R., Sungailienė R., Vilkevičiūtė A., Kriaučiūnienė L., Vaitkienė P., Chaleckis R., Deltuva V.P. Associations between CYP2C8 rs10509681 and rs11572080 gene polymorphisms and age‑related macular degeneration. Acta Med Litu. 2017;24(2):75–82. DOI: 10.6001/actamedica.v24i2.3487
12. Klein R., Lee K.E., Tsai M.Y., Cruickshanks K.J., Gangnon R.E., Klein B.E.K. Oxidized Low‑density Lipoprotein and the Incidence of Age‑related Macular Degeneration. Ophthalmology. 2019;126(5):752–758. DOI: 10.1016/j.ophtha.2018.12.026
13. Jonasson F., Fisher D.E., Eiriksdottir G., Sigurdsson S., Klein R., Launer L.J., Harris T., Gudnason V., Cotch M.F. Five‑year incidence, progression, and risk factors for age‑related macular degeneration: the age, gene/environment susceptibility study. Ophthalmology. 2014;121:1766–1772. DOI: 10.1016/j.ophtha.2014.03.013
14. Yanagi Y., Foo V.H.X., Yoshida A. Asian age‑related macular degeneration: from basic science research perspective. Eye (Lond). 2019; 33(1):34–49. DOI: 10.1038/s41433‑018‑0225‑x
15. Algvere P.V., Kvanta A., Seregard S. Drusen maculopathy: a risk factor for visual deterioration. Acta Ophthalmol. 2016;94(5):427–433. DOI: 10.1111/aos.13011
16. Cai H., Gong J., Abriola L., Hoyer D., Stem Cell Array Team N.G., Noggle S., Paull D., Del Priore L.V., Fields M.A. High‑throughput screening identifies compounds that protect RPE cells from physiological stressors present in AMD. Exp Eye Res. 2019. PII: S0014‑4835(18)30703‑6. DOI: 10.1016/j.exer.2019.04.009
17. Liang X., Wang Z., Gao M., Wu S., Zhang J., Liu Q., Yu Y., Wang J., Liu W. Cyclic stretch induced oxidative stress by mitochondrial and NADPH oxidase in retinal pigment epithelial cells. BMC Ophthalmol. 2019;19(1):79. DOI: 10.1186/s12886‑019‑1087‑0
18. Suzuki M., Kamei M., Itabe H., Yoneda K., Bando H., Kume N., Tano Y. Oxidized phospholipids in the macula increase with age and in eyes with age‑related macular degeneration. Mol Vis. 2007;13:772–778.
19. Ebrahimi K.B., Fijalkowski N., Cano M., Handa J.T. Decreased membrane complement regulators in the retinal pigmented epithelium contributes to age‑related macular degeneration. J. Pathol. 2013;229:729–742. DOI: 10.1002/path.4128
20. Gu X., Meer S.G., Miyagi M., Rayborn M.E., Hollyfield J.G., Crabb J.W., Salomon R.G. Carboxyethylpyrrole protein adducts and autoantibodies, biomarkers for age‑related macular degeneration. J Biol Chem. 2003;278:42027–42035.
21. Domalpally A., Clemons T.E., Danis R.P., Sadda S.R., Cukras C.A., Toth C.A., Friberg T.R., Chew E.Y. Peripheral Retinal Changes Associated with Age‑Related Macular Degeneration in the Age‑Related Eye Disease Study 2: Age‑Related Eye Disease Study 2 Report Number 12 by the Age‑Related Eye Disease Study 2 Optos PEripheral RetinA (OPERA) Study Research Group. Ophthalmology. 2017;124(4):479‑487. DOI: 10.1016/j.ophtha.2016.12.004
22. Fuhrmann S., Zou C., Levine E.M. Retinal pigment epithelium development, plasticity, and tissue homeostasis. Exp Eye Res. 2014;123:141–150. DOI: 10.1016/j.exer.2013.09.003
23. Tserentsoodol N., Sztein J., Campos M., Gordiyenko N.V., Fariss R.N., Lee J.W., Fliesler S.J., Rodriguez I.R. Uptake of cholesterol by the retina occurs primarily via a low density lipoprotein receptormediated process. Mol Vis. 2006;12:1306–1318.
24. van der Schaft T.L., Mooy C.M., de Bruijn W.C., Bosman F.T., de Jong P.T. Immuno-histochemical light and electron microscopy of basal laminar deposit. Graefes Arch Clin Exp Ophthalmol. 1994;232:40–46.
25. Balaratnasingam C., Cherepanoff S., Dolz‑Marco R., Killingsworth M., Chen F.K., Mendis R., Mrejen S., Too L.K., Gal‑Or O., Curcio C.A., Freund K.B., Yannuzzi L.A. Cuticular drusen: clinical phenotypes and natural history defined using multimodal imaging. Ophthalmology. 2018;125(1):100–118. DOI: 10.1016/j.ophtha.2017.08.033
26. Pikuleva I.A., Curcio C.A. Cholesterol in the retina: the best is yet to come. Prog Retin Eye Res. 2014; 41:64–89. DOI: 10.1016/j.preteyeres.2014.03.002
27. Curcio C.A. Soft Drusen in Age‑Related Macular Degeneration: Biology and Targeting Via the Oil Spill Strategies. Invest Ophthalmol Vis Sci. 2018;59(4):AMD160–AMD181. DOI: 10.1167/iovs.18‑24882
28. Oak A.S., Messinger J.D., Curcio C.A. Subretinal drusenoid deposits: further characterization by lipid histochemistry. Retina. 2014;34:825–826. DOI: 10.1097/IAE.0000000000000121
29. Ferris F.L., Wilkinson C.P., Bird A., Chakravarthy U., Chew E., Csaky K., Sadda S.R. Clinical classification of age‑related macular degeneration. Ophthalmology. 2013;120(4):844–851. DOI: 10.1016/j.ophtha.2012.10.036
30. Brandstetter C., Patt J., Holz F.G., Krohne T.U. Inflammasome priming increases retinal pigment epithelial cell susceptibility to lipofuscin phototoxicity by changing the cell death mechanism from apoptosis to pyroptosis. J Photochem Photobiol B. 2016;161:177–183. DOI: 10.1016/j.jphotobiol.2016.05.018
31. Wu T., Tian J., Cutler R.G., Telljohann R.S., Bernlohr D.A., Mattson M.P., Handa J.T. Knockdown of FABP5 mRNA decreases cellular cholesterol levels and results in decreased apoB100 secretion and triglyceride accumulation in ARPE‑19 cells. Lab Invest. 2010;90:963–965. DOI: 10.1038/labinvest.2010.87
32. Storti F., Raphael G., Griesser V., Klee K., Drawne F. Regulated efflux of photoreceptor outer segment‑derived cholesterol by human RPE cells. Exp. Eye Res. 2017;165:65–77. DOI: 10.1016/j.exer.2017.09.008
33. Alamri A., Biswas L., Watson D.G., Shu X. Deletion of TSPO resulted in change of metabolomic profile in retinal pigment epithelial cells. Int J Mol Sci. 2019;20(6). PII: E1387. DOI: 10.3390/ijms20061387
34. Mitter S.K., Song C., Qi X., Mao H., Rao H., Akin D., Lewin A., Grant M., Dunn W. Jr., Ding J., Bowes Rickman C., Boulton M. Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD. Autophagy. 2014;10(11):1989–2005. DOI: 10.4161/auto.36184
35. Hyttinen J.M.T., Błasiak J., Niittykoski M., Kinnunen K., Kauppinen A., Salminen A., Kaarniranta K. DNA damage response and autophagy in the degeneration of retinal pigment epithelial cells‑Implications for age‑related macular degeneration (AMD). Ageing Res Rev. 2017;36:64–77. DOI: 10.1016/j.arr.2017.03.006
36. Qin S., De Vries G.W. alpha2 but not alpha1 AMP‑activated protein kinase mediates oxidative stress‑induced inhibition of retinal pigment epithelium cell phagocytosis of photoreceptor outer segments. J Biol Chem. 2008; 283(11):6744–6751. DOI: 10.1074/jbc.M708848200
37. Mitchell C.H. Release of ATP by a human retinal pigment epithelial cell line: potential for autocrine stimulation through subretinal space. J Physiol. 2001;534(Pt 1):193–202.
38. Reigada D., Zhang X., Crespo A., Nguyen J., Liu J., Pendrak K., Stone R.A., Laties A.M., Mitchell C. Stimulation of an alpha1‑adrenergic receptor downregulates ecto‑5’ nucleotidase activity on the apical membrane of RPE cells. Purinergic Signal. 2006;2(3):499–507. DOI: 10.1007/s11302‑005‑3980‑7
39. Guha S., Baltazar G.C., Coffey E.E., Tu L.A., Lim J.C., Beckel J.M., Patel S., Eysteinsson T., Lu W., O’Brien‑Jenkins A., Laties A.M., Mitchell C.H. Lysosomal alkalinization, lipid oxidation, and reduced phagosome clearance triggered by activation of the P2X7 receptor. FASEB J. 2013; 27(11):4500–4509. DOI: 10.1096/fj.13‑236166
40. Sanderson J., Dartt D.A., Trinkaus‑Randall V., Pintor J., Civan M.M., Delamere N.A., Fletcher E.L., Salt T.E., Grosche A., Mitchell C.H. Purines in the eye: recent evidence for the physiological and pathological role of purines in the RPE, retinal neurons, astrocytes, Müller cells, lens, trabecular meshwork, cornea and lacrimal gland. Exp Eye Res. 2014;127:270–279. DOI: 10.1016/j.exer.2014.08.009
41. Madeira M.H., Rashid K., Ambrósio A.F., Santiago A.R., Langmann T. Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE‑19 cell dysfunction and prevents photoreceptor loss in vitro. Sci Rep. 2018;8(1):2272. DOI: 10.1038/s41598‑018‑20733‑2
42. Cherepanoff S., McMenamin P., Gillies M.C., Kettle E., Sarks S.H. Bruch’s membrane and choroidal macrophages in early and advanced age‑related macular degeneration. Br J Ophthalmol. 2010;94:918–925. DOI: 10.1136/bjo.2009.165563
43. Ban N., Lee T.J., Sene A., Choudhary M., Lekwuwa M., Dong Z., Santeford A., Lin J.B., Malek G., Ory D.S., Apte R.S. Impaired monocyte cholesterol clearance initiates age‑related retinal degeneration and vision loss. JCI Insight. 2018;3(17). PII: 120824. DOI: 10.1172/jci.insight.120824
44. Sene A., Khan A.A., Cox D., Nakamura R.E., Santeford A., Kim B.M., Sidhu R., Onken M.D., Harbour J.W., Hagbi‑Levi S., Chowers I., Edwards P.A, Baldan A., Parks J.S., Ory D.S., Apte R.S. Impaired cholesterol efflux in senescent macrophages promotes age‑related macular degeneration. Cell Metab. 2013; 17:549–561. DOI: 10.1016/j.cmet.2013.03.009
45. Biswas L., Farhan F., Reilly J., Bartholomew C., Shu X. TSPO Ligands Promote Cholesterol Efflux and Suppress Oxidative Stress and Inflammation in Choroidal Endothelial Cells. Int J Mol Sci. 2018;19(12). PII: E3740. DOI: 10.3390/ijms19123740
Review
For citations:
Barinov E.F. Molecular Mechanisms of Druze Formation in the Retina in Age-Related Macular Degeneration. Ophthalmology in Russia. 2020;17(3s):550-555. (In Russ.) https://doi.org/10.18008/1816-5095-2020-3S-550-555
Views:
1230
Email this article 