Asian age-related macular degeneration: from basic science research perspective

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Abstract

In Asian populations, polypoidal choroidal vasculopathy (PCV), a distinct phenotype of neovascular age-related macular degeneration (AMD), is more prevalent than Caucasians. Recently, there has been significant focus on how PCV differs from typical AMD. Although typical AMD and PCV share a variety of mechanisms by which abnormal angiogenic process occurs at the retinochoroidal interface, PCV has different clinical characteristics such as aneurysm-like dilation at the terminal of choroidal neovascular membranes, less frequent drusen and inner choroidal degeneration due to the thickened choroid. Recent studies support an important role for inflammation, angiogenesis molecules and lipid metabolism in the pathogenesis of neovascular AMD. Furthermore, although less attention has been paid to the role of the choroid in AMD, accumulating evidence suggests that the choriocapillaris and choroid also play a pivotal role in drusenogenesis, typical AMD and PCV. This review discusses the basic pathogenic mechanisms of AMD and explores the difference between typical AMD and PCV.

摘要

息肉状脉络膜血管病变 (PCV) 是新生血管性年龄相关性黄斑变性 (AMD) 的一种特殊表型, 好发于亚洲人群, 较高加索人更为常见。近年来研究集中关注于PCV与典型AMD的不同之处。尽管典型AMD和PCV在视网膜脉络膜交界面异常血管生成的过程中具有多种相似的发病机制, 但PCV具有不同的临床特征, 如脉络膜新生血管末端瘤样扩张, 由脉络膜肥厚引起的内层脉络膜变性, 较少见玻璃膜疣等。最新研究提出, 炎症、血管生成因子和脂类代谢均在新生血管性AMD的发生中起到重要作用。此外, 虽然研究较少关注脉络膜在AMD中的作用, 但是大量证据表明脉络膜毛细血管和脉络膜在典型AMD和PCV玻璃膜疣发生中起到关键作用。本综述讨论了AMD的基本发病机制, 探讨了典型AMD和PCV之间的差异。

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References

  1. 1.

    Wong WL, Su X, Li X, Cheung CM, Klein R, Cheng CY, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2:e106–116.

  2. 2.

    Maruko I, Iida T, Saito M, Nagayama D, Saito K. Clinical characteristics of exudative age-related macular degeneration in Japanese patients. Am J Ophthalmol. 2007;144:15–22.

  3. 3.

    Mori K, Horie-Inoue K, Gehlbach PL, Takita H, Kabasawa S, Kawasaki I, et al. Phenotype and genotype characteristics of age-related macular degeneration in a Japanese population. Ophthalmology. 2010;117:928–38.

  4. 4.

    Bird AC, Bressler NM, Bressler SB, Chisholm IH, Coscas G, Davis MD, et al. An international classification and grading system for age-related maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group. Surv Ophthalmol. 1995;39:367–74.

  5. 5.

    Koh AH, Expert PCVP, Chen LJ, Chen SJ, Chen Y, Giridhar A, et al. Polypoidal choroidal vasculopathy: evidence-based guidelines for clinical diagnosis and treatment. Retina. 2013;33:686–716.

  6. 6.

    Okubo A, Sameshima M, Uemura A, Kanda S, Ohba N. Clinicopathological correlation of polypoidal choroidal vasculopathy revealed by ultrastructural study. Br J Ophthalmol. 2002;86:1093–8.

  7. 7.

    Nakashizuka H, Mitsumata M, Okisaka S, Shimada H, Kawamura A, Mori R, et al. Clinicopathologic findings in polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci. 2008;49:4729–37.

  8. 8.

    Gal-Or O, Dansingani KK, Sebrow D, Dolz-Marco R, Freund KB. Inner choroidal flow signal attenuation in pachychoroid disease: optical coherence tomography angiography. Retina. 2018;38:1984–1992.

  9. 9.

    Chung H, Byeon SH, Freund KB. Focal choroidal excavation and its association with pachychoroid spectrum disorders: a review of the literature and multimodal imaging findings. Retina. 2017;37:199–221.

  10. 10.

    Takahashi A, Ooto S, Yamashiro K, Tamura H, Oishi A, Miyata M, et al. Pachychoroid geographic atrophy. Ophthalmol Retina. 2018;2:295–305.

  11. 11.

    Lee JH, Park HY, Baek J, Lee WK. Alterations of the lamina cribrosa are associated with peripapillary retinoschisis in glaucoma and pachychoroid spectrum disease. Ophthalmology. 2016;123:2066–76.

  12. 12.

    Phasukkijwatana N, Freund KB, Dolz-Marco R, Al-Sheikh M, Keane PA, Egan CA et al. Peripapillary Pachychoroid Syndrome. Retina. 2017; Publish Ahead of Print: 1.2018;38;9:1652-67.

  13. 13.

    Spaide RF. Disease expression in nonexudative age-related macular degeneration varies with choroidal thickness. Retina. 2018;38:708–16.

  14. 14.

    Fan Q, Cheung CMG, Chen LJ, Yamashiro K, Ahn J, Laude A, et al. Shared genetic variants for polypoidal choroidal vasculopathy and typical neovascular age-related macular degeneration in East Asians. J Hum Genet. 2017;62:1049–55.

  15. 15.

    Huang L, Zhang H, Cheng CY, Wen F, Tam PO, Zhao P, et al. A missense variant in FGD6 confers increased risk of polypoidal choroidal vasculopathy. Nat Genet. 2016;48:640–7.

  16. 16.

    Cheng CY, Yamashiro K, Chen LJ, Ahn J, Huang L, Huang L, et al. New loci and coding variants confer risk for age-related macular degeneration in East Asians. Nat Commun. 2015;6:6063.

  17. 17.

    Momozawa Y, Akiyama M, Kamatani Y, Arakawa S, Yasuda M, Yoshida S, et al. Low-frequency coding variants in CETP and CFB are associated with susceptibility of exudative age-related macular degeneration in the Japanese population. Hum Mol Genet. 2016;25:5027–34.

  18. 18.

    Ueta T, Iriyama A, Francis J, Takahashi H, Adachi T, Obata R, et al. Development of typical age-related macular degeneration and polypoidal choroidal vasculopathy in fellow eyes of Japanese patients with exudative age-related macular degeneration. Am J Ophthalmol. 2008;146:96–101.

  19. 19.

    Nomura Y, Ueta T, Iriyama A, Inoue Y, Obata R, Tamaki Y, et al. Vitreomacular interface in typical exudative age-related macular degeneration and polypoidal choroidal vasculopathy. Ophthalmology. 2011;118:853–9.

  20. 20.

    Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res. 2001;20:705–32.

  21. 21.

    Bhutto I, Lutty G. Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch’s membrane/choriocapillaris complex. Mol Aspects Med. 2012;33:295–317.

  22. 22.

    Korte GE, D’Aversa G. The elastic tissue of Bruch’s membrane. Arch Ophthalmol. 1989;107:1654–8.

  23. 23.

    Green WR, Enger C. Age-related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology. 1993;100:1519–35.

  24. 24.

    Pauleikhoff D, Harper CA, Marshall J, Bird AC. Aging changes in Bruch’s membrane. A histochemical and morphologic study. Ophthalmology. 1990;97:171–8.

  25. 25.

    Marshall GE, Konstas AG, Lee WR. Collagens in ocular tissues. Br J Ophthalmol. 1993;77:515–24.

  26. 26.

    Holz FG, Sheraidah G, Pauleikhoff D, Bird AC. Analysis of lipid deposits extracted from human macular and peripheral Bruch’s membrane. Arch Ophthalmol. 1994;112:402–6.

  27. 27.

    Handa JT, Verzijl N, Matsunaga H, Aotaki-Keen A, Lutty GA, te Koppele JM, et al. Increase in the advanced glycation end product pentosidine in Bruch’s membrane with age. Invest Ophthalmol Vis Sci. 1999;40:775–9.

  28. 28.

    Sarks SH. Ageing and degeneration in the macular region: a clinico-pathological study. Br J Ophthalmol. 1976;60:324–41.

  29. 29.

    Ueta T, Obata R, Inoue Y, Iriyama A, Takahashi H, Yamaguchi T, et al. Background comparison of typical age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese patients. Ophthalmology. 2009;116:2400–6.

  30. 30.

    Fujimura S, Ueta T, Takahashi H, Obata R, Smith RT, Yanagi Y. Characteristics of fundus autofluorescence and drusen in the fellow eyes of Japanese patients with exudative age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2013;251:1–9.

  31. 31.

    Nickla DL, Wallman J. The multifunctional choroid. Prog Retin Eye Res. 2010;29:144–68.

  32. 32.

    Gelfand BD, Ambati J. A revised hemodynamic theory of age-related macular degeneration. Trends Mol Med. 2016;22:656–70.

  33. 33.

    Ramrattan RS, van der Schaft TL, Mooy CM, de Bruijn WC, Mulder PG, de Jong PT. Morphometric analysis of Bruch’s membrane, the choriocapillaris, and the choroid in aging. Invest Ophthalmol Vis Sci. 1994;35:2857–64.

  34. 34.

    Friedman E, Smith TR, Kuwabara T. Senile choroidal vascular patterns and drusen. Arch Ophthalmol. 1963;69:220–30.

  35. 35.

    Ross RD, Barofsky JM, Cohen G, Baber WB, Palao SW, Gitter KA. Presumed macular choroidal watershed vascular filling, choroidal neovascularization, and systemic vascular disease in patients with age-related macular degeneration. Am J Ophthalmol. 1998;125:71–80.

  36. 36.

    Grunwald JE, Metelitsina TI, Dupont JC, Ying GS, Maguire MG. Reduced foveolar choroidal blood flow in eyes with increasing AMD severity. Invest Ophthalmol Vis Sci. 2005;46:1033–8.

  37. 37.

    Xu W, Grunwald JE, Metelitsina TI, DuPont JC, Ying GS, Martin ER, et al. Association of risk factors for choroidal neovascularization in age-related macular degeneration with decreased foveolar choroidal circulation. Am J Ophthalmol. 2010;150:40–47 e42.

  38. 38.

    Alasil T, Ferrara D, Adhi M, Brewer E, Kraus MF, Baumal CR, et al. En face imaging of the choroid in polypoidal choroidal vasculopathy using swept-source optical coherence tomography. Am J Ophthalmol. 2015;159:634–43.

  39. 39.

    Dansingani KK, Balaratnasingam C, Naysan J, Freund KB. En face imaging of pachychoroid spectrum disorders with swept-source optical coherence tomography. Retina. 2016;36:499–516.

  40. 40.

    Ferrara D, Waheed NK, Duker JS. Investigating the choriocapillaris and choroidal vasculature with new optical coherence tomography technologies. Prog Retin Eye Res. 2016;52:130–55.

  41. 41.

    Anderson DH, Radeke MJ, Gallo NB, Chapin EA, Johnson PT, Curletti CR, et al. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res. 2010;29:95–112.

  42. 42.

    Mullins RF, Schoo DP, Sohn EH, Flamme-Wiese MJ, Workamelahu G, Johnston RM, et al. The membrane attack complex in aging human choriocapillaris: relationship to macular degeneration and choroidal thinning. Am J Pathol. 2014;184:3142–53.

  43. 43.

    Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol. 2002;134:411–31.

  44. 44.

    Yuda K, Takahashi H, Inoue T, Ueta T, Iriyama A, Kadonosono K, et al. Adrenomedullin inhibits choroidal neovascularization via CCL2 in the retinal pigment epithelium. Am J Pathol. 2012;181:1464–72.

  45. 45.

    Bhutto IA, Baba T, Merges C, Juriasinghani V, McLeod DS, Lutty GA. C-reactive protein and complement factor H in aged human eyes and eyes with age-related macular degeneration. Br J Ophthalmol. 2011;95:1323–30.

  46. 46.

    Johnson PT, Betts KE, Radeke MJ, Hageman GS, Anderson DH, Johnson LV. Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid. Proc Natl Acad Sci USA. 2006;103:17456–61.

  47. 47.

    McLeod DS, Lefer DJ, Merges C, Lutty GA. Enhanced expression of intracellular adhesion molecule-1 and P-selectin in the diabetic human retina and choroid. Am J Pathol. 1995;147:642–53.

  48. 48.

    Skeie JM, Fingert JH, Russell SR, Stone EM, Mullins RF. Complement component C5a activates ICAM-1 expression on human choroidal endothelial cells. Invest Ophthalmol Vis Sci. 2010;51:5336–42.

  49. 49.

    Aboelnour A, Kam JH, Elnasharty MA, Sayed-Ahmed A, Jeffery G. Amyloid beta deposition and phosphorylated tau accumulation are key features in aged choroidal vessels in the complement factor H knock out model of retinal degeneration. Exp Eye Res. 2016;147:138–43.

  50. 50.

    Cherepanoff S, McMenamin P, Gillies MC, Kettle E, Sarks SH. Bruch’s membrane and choroidal macrophages in early and advanced age-related macular degeneration. Br J Ophthalmol. 2010;94:918–25.

  51. 51.

    Tan X, Fujiu K, Manabe I, Nishida J, Yamagishi R, Nagai R, et al. Choroidal neovascularization is inhibited via an intraocular decrease of inflammatory cells in mice lacking complement component C3. Sci Rep. 2015;5:15702.

  52. 52.

    Tan X, Fujiu K, Manabe I, Nishida J, Yamagishi R, Terashima Y, et al. Choroidal neovascularization is inhibited in splenic-denervated or splenectomized mice with a concomitant decrease in intraocular macrophage. PLoS One. 2016;11:e0160985.

  53. 53.

    Bhutto IA, McLeod DS, Jing T, Sunness JS, Seddon JM, Lutty GA. Increased choroidal mast cells and their degranulation in age-related macular degeneration. Br J Ophthalmol. 2016;100:720–6.

  54. 54.

    Datta S, Cano M, Ebrahimi K, Wang L, Handa JT. The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD. Prog Retin Eye Res. 2017;60:201–18.

  55. 55.

    Doyle SL, Campbell M, Ozaki E, Salomon RG, Mori A, Kenna PF, et al. NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components. Nat Med. 2012;18:791–8.

  56. 56.

    Tarallo V, Hirano Y, Gelfand BD, Dridi S, Kerur N, Kim Y, et al. DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell. 2012;149:847–59.

  57. 57.

    Kerur N, Fukuda S, Banerjee D, Kim Y, Fu D, Apicella I, et al. cGAS drives noncanonical-inflammasome activation in age-related macular degeneration. Nat Med. 2018;24:50–61.

  58. 58.

    Kosmidou C, Efstathiou NE, Hoang MV, Notomi S, Konstantinou EK, Hirano M, et al. Issues with the specificity of immunological reagents for NLRP3: implications for age-related macular degeneration. Sci Rep. 2018;8:461.

  59. 59.

    Hong YJ, Miura M, Makita S, Ju MJ, Lee BH, Iwasaki T, et al. Noninvasive investigation of deep vascular pathologies of exudative macular diseases by high-penetration optical coherence angiography. Invest Ophthalmol Vis Sci. 2013;54:3621–31.

  60. 60.

    Fritsche LG, Igl W, Bailey JN, Grassmann F, Sengupta S, Bragg-Gresham JL, et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016;48:134–43.

  61. 61.

    Ando A, Yang A, Mori K, Yamada H, Yamada E, Takahashi K, et al. Nitric oxide is proangiogenic in the retina and choroid. J Cell Physiol. 2002;191:116–24.

  62. 62.

    Cheung CM, Laude A, Yeo I, Tan SP, Fan Q, Mathur R, et al. Systemic, ocular and genetic risk factors for age-related macular degeneration and polypoidal choroidal vasculopathy in Singaporeans. Sci Rep. 2017;7:41386.

  63. 63.

    Reynolds R, Rosner B, Seddon JM. Serum lipid biomarkers and hepatic lipase gene associations with age-related macular degeneration. Ophthalmology. 2010;117:1989–95.

  64. 64.

    Burgess S, Davey Smith G. Mendelian randomization implicates high-density lipoprotein cholesterol-associated mechanisms in etiology of age-related macular degeneration. Ophthalmology. 2017;124:1165–74.

  65. 65.

    Curcio CA, Johnson M, Huang JD, Rudolf M. Aging, age-related macular degeneration, and the response-to-retention of apolipoprotein B-containing lipoproteins. Prog Retin Eye Res. 2009;28:393–422.

  66. 66.

    Pikuleva IA, Curcio CA. Cholesterol in the retina: the best is yet to come. Prog Retin Eye Res. 2014;41:64–89.

  67. 67.

    Ishida BY, Duncan KG, Bailey KR, Kane JP, Schwartz DM. High density lipoprotein mediated lipid efflux from retinal pigment epithelial cells in culture. Br J Ophthalmol. 2006;90:616–20.

  68. 68.

    Storti F, Raphael G, Griesser V, Klee K, Drawnel F, Willburger C, et al. Regulated efflux of photoreceptor outer segment-derived cholesterol by human RPE cells. Exp Eye Res. 2017;165:65–77.

  69. 69.

    Picard E, Houssier M, Bujold K, Sapieha P, Lubell W, Dorfman A, et al. CD36 plays an important role in the clearance of oxLDL and associated age-dependent sub-retinal deposits. Aging. 2010;2:981–9.

  70. 70.

    Vavvas DG, Daniels AB, Kapsala ZG, Goldfarb JW, Ganotakis E, Loewenstein JI, et al. Regression of some high-risk features of age-related macular degeneration (AMD) in patients receiving intensive statin treatment. EBioMedicine. 2016;5:198–203.

  71. 71.

    Rudolf M, Mir Mohi Sefat A, Miura Y, Tura A, Raasch W, Ranjbar M, et al. ApoA-I mimetic peptide 4F reduces age-related lipid deposition in murine bruch’s membrane and causes its structural remodeling. Curr Eye Res. 2018;43:135–46.

  72. 72.

    Talbot CPJ, Plat J, Ritsch A, Mensink RP. Determinants of cholesterol efflux capacity in humans. Prog Lipid Res. 2018;69:21–32.

  73. 73.

    Sene A, Khan AA, Cox D, Nakamura R, Santeford A, Kim BM, et al. Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration. Cell Metab. 2013;17:549–61.

  74. 74.

    Joyal JS, Sun Y, Gantner ML, Shao Z, Evans LP, Saba N, et al. Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1. Nat Med. 2016;22:439–45.

  75. 75.

    Coffey PJ, Gias C, McDermott CJ, Lundh P, Pickering MC, Sethi C, et al. Complement factor H deficiency in aged mice causes retinal abnormalities and visual dysfunction. Proc Natl Acad Sci USA. 2007;104:16651–6.

  76. 76.

    Ufret-Vincenty RL, Aredo B, Liu X, McMahon A, Chen PW, Sun H, et al. Transgenic mice expressing variants of complement factor H develop AMD-like retinal findings. Invest Ophthalmol Vis Sci. 2010;51:5878–87.

  77. 77.

    Dithmar S, Curcio CA, Le NA, Brown S, Grossniklaus HE. Ultrastructural changes in Bruch’s membrane of apolipoprotein E-deficient mice. Invest Ophthalmol Vis Sci. 2000;41:2035–42.

  78. 78.

    Malek G, Johnson LV, Mace BE, Saloupis P, Schmechel DE, Rickman DW, et al. Apolipoprotein E allele-dependent pathogenesis: a model for age-related retinal degeneration. Proc Natl Acad Sci USA. 2005;102:11900–5.

  79. 79.

    Imamura Y, Noda S, Hashizume K, Shinoda K, Yamaguchi M, Uchiyama S, et al. Drusen, choroidal neovascularization, and retinal pigment epithelium dysfunction in SOD1-deficient mice: a model of age-related macular degeneration. Proc Natl Acad Sci USA. 2006;103:11282–7.

  80. 80.

    Justilien V, Pang JJ, Renganathan K, Zhan X, Crabb JW, Kim SR, et al. SOD2 knockdown mouse model of early AMD. Invest Ophthalmol Vis Sci. 2007;48:4407–20.

  81. 81.

    Mattapallil MJ, Wawrousek EF, Chan CC, Zhao H, Roychoudhury J, Ferguson TA, et al. The Rd8 mutation of the Crb1 gene is present in vendor lines of C57BL/6N mice and embryonic stem cells, and confounds ocular induced mutant phenotypes. Invest Ophthalmol Vis Sci. 2012;53:2921–7.

  82. 82.

    Iejima D, Nakayama M, Iwata T. HTRA1 overexpression induces the exudative form of age-related macular degeneration. J Stem Cells. 2015;10:193–203.

  83. 83.

    Ng TK, Liang XY, Lai TY, Ma L, Tam PO, Wang JX, et al. HTRA1 promoter variant differentiates polypoidal choroidal vasculopathy from exudative age-related macular degeneration. Sci Rep. 2016;6:28639.

  84. 84.

    Liao S-MM, Zheng W, Zhu J, Lewis CA, Delgado O, Crowley MA, et al. Specific correlation between the major chromosome 10q26 haplotype conferring risk for age-related macular degeneration and the expression ofHTRA1. Mol Vis. 2017;23:318–33.

  85. 85.

    Nakayama M, Iejima D, Akahori M, Kamei J, Goto A, Iwata T. Overexpression of HtrA1 and exposure to mainstream cigarette smoke leads to choroidal neovascularization and subretinal deposits in aged mice. Invest Ophthalmol Vis Sci. 2014;55:6514–23.

  86. 86.

    Jones A, Kumar S, Zhang N, Tong Z, Yang JH, Watt C, et al. Increased expression of multifunctional serine protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal vasculopathy in mice. Proc Natl Acad Sci USA. 2011;108:14578–83.

  87. 87.

    Vierkotten S, Muether PS, Fauser S. Overexpression of HTRA1 leads to ultrastructural changes in the elastic layer of Bruch’s membrane via cleavage of extracellular matrix components. PLoS ONE. 2011;6:e22959.

  88. 88.

    Poepsel S, Sprengel A, Sacca B, Kaschani F, Kaiser M, Gatsogiannis C, et al. Determinants of amyloid fibril degradation by the PDZ protease HTRA1. Nat Chem Biol. 2015;11:862–9.

  89. 89.

    Chu Q, Diedrich JK, Vaughan JM, Donaldson CJ, Nunn MF, Lee KF, et al. HtrA1 proteolysis of ApoE in vitro is allele selective. J Am Chem Soc. 2016;138:9473–8.

  90. 90.

    Munoz SS, Li H, Ruberu K, Chu Q, Saghatelian A, Ooi L, et al. The serine protease HtrA1 contributes to the formation of an extracellular 25-kDa apolipoprotein E fragment that stimulates neuritogenesis. J Biol Chem. 2018;293:4071–84.

  91. 91.

    Chen CY, Melo E, Jakob P, Friedlein A, Elsasser B, Goettig P. et al. N-Terminomics identifies HtrA1 cleavage of thrombospondin-1 with generation of a proangiogenic fragment in the polarized retinal pigment epithelial cell model of age-related macular degeneration. Matrix Biol. 2018;70:84–101.

  92. 92.

    Globus O, Evron T, Caspi M, Siman-Tov R, Rosin-Arbesfeld R. High-temperature requirement A1 (Htra1) - a novel regulator of canonical Wnt signaling. Sci Rep. 2017;7:17995.

  93. 93.

    Kim GY, Kim HY, Kim HT, Moon JM, Kim CH, Kang S, et al. HtrA1 is a novel antagonist controlling fibroblast growth factor (FGF) signaling via cleavage of FGF8. Mol Cell Biol. 2012;32:4482–92.

  94. 94.

    Fex Svenningsen A, Loring S, Sorensen AL, Huynh HUB, Hjaeresen S, Martin N, et al. Macrophage migration inhibitory factor (MIF) modulates trophic signaling through interaction with serine protease HTRA1. Cell Mol Life Sci. 2017;74:4561–72.

  95. 95.

    Chien J, Ota T, Aletti G, Shridhar R, Boccellino M, Quagliuolo L, et al. Serine protease HtrA1 associates with microtubules and inhibits cell migration. Mol Cell Biol. 2009;29:4177–87.

  96. 96.

    Melo E, Oertle P, Trepp C, Meistermann H, Burgoyne T, Sborgi L, et al. HtrA1 mediated intracellular effects on tubulin using a polarized RPE disease model. EBioMedicine. 2018;27:258–74.

  97. 97.

    Kumar S, Nakashizuka H, Jones A, Lambert A, Zhao X, Shen M, et al. Proteolytic degradation and inflammation play critical roles in polypoidal choroidal vasculopathy. Am J Pathol. 2017;187:2841–57.

  98. 98.

    Zhang L, Lim SL, Du H, Zhang M, Kozak I, Hannum G, et al. High temperature requirement factor A1 (HTRA1) gene regulates angiogenesis through transforming growth factor-beta family member growth differentiation factor 6. J Biol Chem. 2012;287:1520–6.

  99. 99.

    Saini JS, Corneo B, Miller JD, Kiehl TR, Wang Q, Boles NC, et al. Nicotinamide ameliorates disease phenotypes in a human iPSC model of age-related macular degeneration. Cell Stem Cell. 2017;20:635–47 e637.

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Acknowledgements

We thank Hiroyuki Nakashizuka (Nihon University) who provided surgical specimen. Figures 3, 4, 5, 6 and 7 were produced, in part, by using Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License. http://smart.servier.com/.

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Correspondence to Yasuo Yanagi.

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Yanagi, Y., Foo, V.H.X. & Yoshida, A. Asian age-related macular degeneration: from basic science research perspective. Eye 33, 34–49 (2019) doi:10.1038/s41433-018-0225-x

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