Advertisement

Cellular and Molecular Life Sciences

, Volume 71, Issue 23, pp 4617–4636 | Cite as

Emerging roles for nuclear receptors in the pathogenesis of age-related macular degeneration

  • Goldis MalekEmail author
  • Eleonora M. Lad
Review

Abstract

Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly in the Western world. Over the last 30 years, our understanding of the pathogenesis of the disease has grown exponentially thanks to the results of countless epidemiology, genetic, histological, and biochemical studies. This information, in turn, has led to the identification of multiple biologic pathways potentially involved in development and progression of AMD, including but not limited to inflammation, lipid and extracellular matrix dysregulation, and angiogenesis. Nuclear receptors are a superfamily of transcription factors that have been shown to regulate many of the pathogenic pathways linked with AMD and as such they are emerging as promising targets for therapeutic intervention. In this review, we will present the fundamental phenotypic features of AMD and discuss our current understanding of the pathobiological disease mechanisms. We will introduce the nuclear receptor superfamily and discuss the current literature on their effects on AMD-related pathophysiology.

Keywords

Drusen Geographic atrophy Choroidal neovascularization Transcription factors Aryl hydrocarbon receptor Liver X receptors Peroxisome proliferator-activated receptors Retinoid X receptors 

Abbreviations

A2E

N-retinyle- din-N-retinylethanolamin

ABCA1

ATP binding cassette subfamily A1

AF

Activation function

AhR

Aryl hydrocarbon receptor

AMD

Age-related macular degeneration

ApoE

Apolipoprotein E

AREDS

Age-related eye disease study

BLamD

Basal laminar deposit

BLinD

Basal linear deposit

CFH

Complement factor H

CNV

Choroidal neovascularization

CYP450

Cytochrome P 450

DBD

DNA-binding domain

DHA

Docosahexaenoic acid

EPA

Eicosapentaenoic acid

ER

Estrogen receptor

GA

Geographic atrophy

GR

Glucocorticoid receptor

GWAS

Genome-wide association study

HDL

High-density lipoprotein

IL

Interleukin

LBD

Ligand-binding domain

LDL

Low-density lipoprotein

LXR

Liver X receptor

NR

Nuclear receptor

NRRE

Nuclear receptor response element

PPAR

Peroxisome proliferator-activated receptor

RAR

Retinoic acid receptors

ROR

Retinoic acid receptor-related orphan receptor

RPD

Reticular pseudodrusen

RPE

Retinal pigment epithelium

RXR

Retinoid X receptor

SD-OCT

Spectral domain-optical coherence tomography

SNP

Single nucleotide polymorphism

TNF

Tumor necrosis factor

VEGF

Vascular endothelial growth factor

Notes

Acknowledgments

Sincere thanks to the North Carolina Eye Bank, the Alabama Eye Bank, the eye donors and their families for their generosity to our group, and others, allowing us and other researchers to collectively understand the disease through their eyes. We would like to thank Mr. Steven Conlon for designing the artwork presented in Fig. 1. This work was supported by the US National Eye Institute grants EY02868 (GM), 5K12EY016333-08 (EL), and P30 EY005722 (Duke University), and the Research to Prevent Blindness, Inc. (RPB) Sybil B. Harrington Scholars Award (GM) and a RPB Core grant to the Duke Eye Center.

References

  1. 1.
    Klein R et al (2013) The relationship of atherosclerosis to the 10-year cumulative incidence of age-related macular degeneration: the Beaver Dam studies. Ophthalmology 120(5):1012–1019PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Rein DB et al (2009) Forecasting age-related macular degeneration through the year 2050: the potential impact of new treatments. Arch Ophthalmol 127(4):533–540PubMedCrossRefGoogle Scholar
  3. 3.
    Davis MD et al (2005) The age-related eye disease study severity scale for age-related macular degeneration: AREDS Report No. 17. Arch Ophthalmol 123(11):1484–1498PubMedCrossRefGoogle Scholar
  4. 4.
    Ferris FL et al (2005) A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol 123(11):1570–1574PubMedCrossRefGoogle Scholar
  5. 5.
    Hee MR et al (1995) Optical coherence tomography of the human retina. Arch Ophthalmol 113(3):325–332PubMedCrossRefGoogle Scholar
  6. 6.
    Puliafito CA et al (1995) Imaging of macular diseases with optical coherence tomography. Ophthalmology 102(2):217–229PubMedCrossRefGoogle Scholar
  7. 7.
    Sohrab MA, Smith RT, Fawzi AA (2011) Imaging characteristics of dry age-related macular degeneration. Semin Ophthalmol 26(3):156–166PubMedCrossRefGoogle Scholar
  8. 8.
    Curcio CA, Millican CL (1999) Basal linear deposit and large drusen are specific for early age-related maculopathy. Arch Ophthalmol 117(3):329–339PubMedCrossRefGoogle Scholar
  9. 9.
    Green WR, Enger C (1993) Age-related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology 100(10):1519–1535PubMedCrossRefGoogle Scholar
  10. 10.
    Loffler KU, Lee WR (1986) Basal linear deposit in the human macula. Graefes Arch Clin Exp Ophthalmol 224(6):493–501PubMedCrossRefGoogle Scholar
  11. 11.
    Sarks S et al (2007) Relationship of Basal laminar deposit and membranous debris to the clinical presentation of early age-related macular degeneration. Invest Ophthalmol Vis Sci 48(3):968–977PubMedCrossRefGoogle Scholar
  12. 12.
    Sarks SH (1976) Ageing and degeneration in the macular region: a clinico-pathological study. Br J Ophthalmol 60(5):324–341PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    van der Schaft TL et al (1993) Early stages of age-related macular degeneration: an immunofluorescence and electron microscopy study. Br J Ophthalmol 77(10):657–661PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Hageman GS et al (2001) 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 20(6):705–732PubMedCrossRefGoogle Scholar
  15. 15.
    Bressler NM et al (1989) The grading and prevalence of macular degeneration in Chesapeake Bay watermen. Arch Ophthalmol 107(6):847–852PubMedCrossRefGoogle Scholar
  16. 16.
    Gregor Z, Bird AC, Chisholm IH (1977) Senile disciform macular degeneration in the second eye. Br J Ophthalmol 61(2):141–147PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Klein R et al (1991) The Wisconsin age-related maculopathy grading system. Ophthalmology 98(7):1128–1134PubMedCrossRefGoogle Scholar
  18. 18.
    Berenberg TL et al (2012) The association between drusen extent and foveolar choroidal blood flow in age-related macular degeneration. Retina 32(1):25–31PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Bhutto I, Lutty G (2012) Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch’s membrane/choriocapillaris complex. Mol Aspects Med 33(4):295–317PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Mullins RF et al (2011) Choriocapillaris vascular dropout related to density of drusen in human eyes with early age-related macular degeneration. Invest Ophthalmol Vis Sci 52(3):1606–1612PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    van der Schaft TL et al (1993) Basal laminar deposit in the aging peripheral human retina. Graefes Arch Clin Exp Ophthalmol 231(8):470–475PubMedCrossRefGoogle Scholar
  22. 22.
    Owsley C et al (2006) Development of a questionnaire to assess vision problems under low luminance in age-related maculopathy. Invest Ophthalmol Vis Sci 47(2):528–535PubMedCrossRefGoogle Scholar
  23. 23.
    Scilley K et al (2002) Early age-related maculopathy and self-reported visual difficulty in daily life. Ophthalmology 109(7):1235–1242PubMedCrossRefGoogle Scholar
  24. 24.
    Mangione CM et al (1999) Influence of age-related maculopathy on visual functioning and health-related quality of life. Am J Ophthalmol 128(1):45–53PubMedCrossRefGoogle Scholar
  25. 25.
    Curcio CA, Medeiros NE, Millican CL (1996) Photoreceptor loss in age-related macular degeneration. Invest Ophthalmol Vis Sci 37(7):1236–1249PubMedGoogle Scholar
  26. 26.
    Medeiros NE, Curcio CA (2001) Preservation of ganglion cell layer neurons in age-related macular degeneration. Invest Ophthalmol Vis Sci 42(3):795–803PubMedGoogle Scholar
  27. 27.
    Holz FG et al (1995) Colour contrast sensitivity in patients with age-related Bruch’s membrane changes. Ger J Ophthalmol 4(6):336–341PubMedGoogle Scholar
  28. 28.
    Cohen SY et al (2007) Prevalence of reticular pseudodrusen in age-related macular degeneration with newly diagnosed choroidal neovascularisation. Br J Ophthalmol 91(3):354–359PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Ooto S et al (2013) Reduction of retinal sensitivity in eyes with reticular pseudodrusen. Am J Ophthalmol 156(6):1184e2–1191e2CrossRefGoogle Scholar
  30. 30.
    Querques G et al (2013) Reticular pseudodrusen. Ophthalmology 120(4):872e4CrossRefGoogle Scholar
  31. 31.
    Schmitz-Valckenberg S et al (2011) Reticular drusen associated with geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci 52(9):5009–5015PubMedCrossRefGoogle Scholar
  32. 32.
    Curcio CA et al (2013) Subretinal drusenoid deposits in non-neovascular age-related macular degeneration: morphology, prevalence, topography, and biogenesis model. Retina 33(2):265–276PubMedCrossRefGoogle Scholar
  33. 33.
    Zweifel SA et al (2010) Prevalence and significance of subretinal drusenoid deposits (reticular pseudodrusen) in age-related macular degeneration. Ophthalmology 117(9):1775–1781PubMedCrossRefGoogle Scholar
  34. 34.
    Zweifel SA et al (2010) Reticular pseudodrusen are subretinal drusenoid deposits. Ophthalmology 117(2):303e1–312e1CrossRefGoogle Scholar
  35. 35.
    Querques G et al (2011) Pathologic insights from integrated imaging of reticular pseudodrusen in age-related macular degeneration. Retina 31(3):518–526PubMedCrossRefGoogle Scholar
  36. 36.
    Arnold JJ et al (1995) Reticular pseudodrusen. A risk factor in age-related maculopathy. Retina 15(3):183–191PubMedCrossRefGoogle Scholar
  37. 37.
    Sarks J et al (2011) Evolution of reticular pseudodrusen. Br J Ophthalmol 95(7):979–985PubMedCrossRefGoogle Scholar
  38. 38.
    Rudolf M et al (2008) Sub-retinal drusenoid deposits in human retina: organization and composition. Exp Eye Res 87(5):402–408PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Smailhodzic D et al (2011) Central areolar choroidal dystrophy (CACD) and age-related macular degeneration (AMD): differentiating characteristics in multimodal imaging. Invest Ophthalmol Vis Sci 52(12):8908–8918PubMedCrossRefGoogle Scholar
  40. 40.
    Smith RT et al (2011) Complement factor H 402H variant and reticular macular disease. Arch Ophthalmol 129(8):1061–1066PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Klein R et al (2008) The epidemiology of retinal reticular drusen. Am J Ophthalmol 145(2):317–326PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Lois N et al (2002) Fundus autofluorescence in patients with age-related macular degeneration and high risk of visual loss. Am J Ophthalmol 133(3):341–349PubMedCrossRefGoogle Scholar
  43. 43.
    Prenner JL et al (2003) Risk factors for choroidal neovascularization and vision loss in the fellow eye study of CNVPT. Retina 23(3):307–314PubMedCrossRefGoogle Scholar
  44. 44.
    Klein ML et al (2008) CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmology 115(6):1019–1025PubMedCrossRefGoogle Scholar
  45. 45.
    Congdon N et al (2004) Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol 122(4):477–485PubMedCrossRefGoogle Scholar
  46. 46.
    Ferris FL 3rd, Fine SL, Hyman L (1984) Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol 102(11):1640–1642PubMedCrossRefGoogle Scholar
  47. 47.
    Friedman DS et al (2004) Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 122(4):564–572PubMedCrossRefGoogle Scholar
  48. 48.
    Alexander MF et al (1988) Assessment of visual function in patients with age-related macular degeneration and low visual acuity. Arch Ophthalmol 106(11):1543–1547PubMedCrossRefGoogle Scholar
  49. 49.
    Williams RA et al (1998) The psychosocial impact of macular degeneration. Arch Ophthalmol 116(4):514–520PubMedCrossRefGoogle Scholar
  50. 50.
    Baird PN et al (2008) Gene-environment interaction in progression of AMD: the CFH gene, smoking and exposure to chronic infection. Hum Mol Genet 17(9):1299–1305PubMedCrossRefGoogle Scholar
  51. 51.
    Tomany SC et al (2004) Risk factors for incident age-related macular degeneration: pooled findings from 3 continents. Ophthalmology 111(7):1280–1287PubMedCrossRefGoogle Scholar
  52. 52.
    Edwards AO, Malek G (2007) Molecular genetics of AMD and current animal models. Angiogenesis 10(2):119–132PubMedCrossRefGoogle Scholar
  53. 53.
    Pennesi ME, Neuringer M, Courtney RJ (2012) Animal models of age related macular degeneration. Mol Aspects Med 33(4):487–509PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Seddon JM (2013) Genetic and environmental underpinnings to age-related ocular diseases. Invest Ophthalmol Vis Sci 54(14):ORSF28–ORSF30PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Seddon JM et al (2009) Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci 50(5):2044–2053PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Seddon JM et al (2011) Risk models for progression to advanced age-related macular degeneration using demographic, environmental, genetic, and ocular factors. Ophthalmology 118(11):2203–2211PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Seddon JM et al (1996) A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA 276(14):1141–1146PubMedCrossRefGoogle Scholar
  58. 58.
    Suner IJ et al (2004) Nicotine increases size and severity of experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 45(1):311–317PubMedCrossRefGoogle Scholar
  59. 59.
    Cho E et al (2001) Prospective study of dietary fat and the risk of age-related macular degeneration. Am J Clin Nutr 73(2):209–218PubMedGoogle Scholar
  60. 60.
    Cho E et al (2004) Prospective study of intake of fruits, vegetables, vitamins, and carotenoids and risk of age-related maculopathy. Arch Ophthalmol 122(6):883–892PubMedCrossRefGoogle Scholar
  61. 61.
    Mares-Perlman JA et al (1995) Dietary fat and age-related maculopathy. Arch Ophthalmol 113(6):743–748PubMedCrossRefGoogle Scholar
  62. 62.
    Seddon JM, Cote J, Rosner B (2003) Progression of age-related macular degeneration: association with dietary fat, transunsaturated fat, nuts, and fish intake. Arch Ophthalmol 121(12):1728–1737PubMedCrossRefGoogle Scholar
  63. 63.
    Seddon JM, Hennekens CH (1994) Vitamins, minerals, and macular degeneration. Promising but unproven hypotheses. Arch Ophthalmol 112(2):176–179CrossRefGoogle Scholar
  64. 64.
    Seddon JM et al (2001) Dietary fat and risk for advanced age-related macular degeneration. Arch Ophthalmol 119(8):1191–1199PubMedCrossRefGoogle Scholar
  65. 65.
    Anderson RE, Rapp LM, Wiegand RD (1984) Lipid peroxidation and retinal degeneration. Curr Eye Res 3(1):223–227PubMedCrossRefGoogle Scholar
  66. 66.
    Young RW (1987) Pathophysiology of age-related macular degeneration. Surv Ophthalmol 31(5):291–306PubMedCrossRefGoogle Scholar
  67. 67.
    Bone RA et al (2003) Lutein and zeaxanthin dietary supplements raise macular pigment density and serum concentrations of these carotenoids in humans. J Nutr 133(4):992–998PubMedGoogle Scholar
  68. 68.
    Krinsky NI, Landrum JT, Bone RA (2003) Biologic mechanisms of the protective role of lutein and zeaxanthin in the eye. Annu Rev Nutr 23:171–201PubMedCrossRefGoogle Scholar
  69. 69.
    Delcourt C et al (2006) Plasma lutein and zeaxanthin and other carotenoids as modifiable risk factors for age-related maculopathy and cataract: the POLA Study. Invest Ophthalmol Vis Sci 47(6):2329–2335PubMedCrossRefGoogle Scholar
  70. 70.
    SanGiovanni JP et al (2007) The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20. Arch Ophthalmol 125(5):671–679PubMedCrossRefGoogle Scholar
  71. 71.
    Aronow ME, Chew EY (2014) Age-related eye disease study 2: perspectives, recommendations, and unanswered questions. Curr Opin Ophthalmol 25(3):186–190PubMedCrossRefGoogle Scholar
  72. 72.
    Hughes DA, Pinder AC (1996) Influence of n-3 polyunsaturated fatty acids (PUFA) on the antigen-presenting function of human monocytes. Biochem Soc Trans 24(3):389SPubMedGoogle Scholar
  73. 73.
    Hughes DA, Southon S, Pinder AC (1996) (n-3) Polyunsaturated fatty acids modulate the expression of functionally associated molecules on human monocytes in vitro. J Nutr 126(3):603–610PubMedGoogle Scholar
  74. 74.
    Luostarinen R, Saldeen T (1996) Dietary fish oil decreases superoxide generation by human neutrophils: relation to cyclooxygenase pathway and lysosomal enzyme release. Prostaglandins Leukot Essent Fatty Acids 55(3):167–172PubMedCrossRefGoogle Scholar
  75. 75.
    Calder PC (2001) omega 3 polyunsaturated fatty acids, inflammation and immunity. World Rev Nutr Diet 88:109–116PubMedCrossRefGoogle Scholar
  76. 76.
    Mukutmoni-Norris M, Hubbard NE, Erickson KL (2000) Modulation of murine mammary tumor vasculature by dietary n-3 fatty acids in fish oil. Cancer Lett 150(1):101–109PubMedCrossRefGoogle Scholar
  77. 77.
    Anderson RE, Penn JS (2004) Environmental light and heredity are associated with adaptive changes in retinal DHA levels that affect retinal function. Lipids 39(11):1121–1124PubMedCrossRefGoogle Scholar
  78. 78.
    Rotstein NP et al (1997) Apoptosis of retinal photoreceptors during development in vitro: protective effect of docosahexaenoic acid. J Neurochem 69(2):504–513PubMedCrossRefGoogle Scholar
  79. 79.
    Writing Group for the A.R.G et al (2014) Effect of long-chain omega-3 fatty acids and lutein + zeaxanthin supplements on cardiovascular outcomes: results of the age-related eye disease study 2 (AREDS2) randomized clinical trial. JAMA. Intern Med 174(5):763–771Google Scholar
  80. 80.
    Curcio CA et al (2001) Accumulation of cholesterol with age in human Bruch’s membrane. Invest Ophthalmol Vis Sci 42(1):265–274PubMedGoogle Scholar
  81. 81.
    Pauleikhoff D et al (1990) Aging changes in Bruch’s membrane. A histochemical and morphologic study. Ophthalmology 97(2):171–178PubMedCrossRefGoogle Scholar
  82. 82.
    van Leeuwen R et al (2004) Cholesterol and age-related macular degeneration: is there a link? Am J Ophthalmol 137(4):750–752PubMedCrossRefGoogle Scholar
  83. 83.
    Reynolds R, Rosner B, Seddon JM (2010) Serum lipid biomarkers and hepatic lipase gene associations with age-related macular degeneration. Ophthalmology 117(10):1989–1995PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Vingerling JR et al (1995) Age-related macular degeneration is associated with atherosclerosis. The Rotterdam Study. Am J Epidemiol 142(4):404–409PubMedGoogle Scholar
  85. 85.
    Anderson DH et al (2002) A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 134(3):411–431PubMedCrossRefGoogle Scholar
  86. 86.
    Johnson LV et al (2001) Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Exp Eye Res 73(6):887–896PubMedCrossRefGoogle Scholar
  87. 87.
    Mullins RF et al (2000) Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J 14(7):835–846PubMedGoogle Scholar
  88. 88.
    Ding JD et al (2011) Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration. Proc Natl Acad Sci USA 108(28):E279–E287PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Malek G et al (2005) Apolipoprotein E allele-dependent pathogenesis: a model for age-related retinal degeneration. Proc Natl Acad Sci USA 102(33):11900–11905PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Crabb JW et al (2002) Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci USA 99(23):14682–14687PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Anderson DH et al (2004) Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration. Exp Eye Res 78(2):243–256PubMedCrossRefGoogle Scholar
  92. 92.
    Dentchev T et al (2003) Amyloid-beta is found in drusen from some age-related macular degeneration retinas, but not in drusen from normal retinas. Mol Vis 9:184–190PubMedGoogle Scholar
  93. 93.
    Gopinath B et al (2013) Homocysteine, folate, vitamin B-12, and 10-y incidence of age-related macular degeneration. Am J Clin Nutr 98(1):129–135PubMedCrossRefGoogle Scholar
  94. 94.
    Reynolds R et al (2009) Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes. Invest Ophthalmol Vis Sci 50(12):5818–5827PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Schaumberg DA et al (2006) A prospective assessment of the Y402H variant in complement factor H, genetic variants in C-reactive protein, and risk of age-related macular degeneration. Invest Ophthalmol Vis Sci 47(6):2336–2340PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Seddon JM et al (2004) Association between C-reactive protein and age-related macular degeneration. JAMA 291(6):704–710PubMedCrossRefGoogle Scholar
  97. 97.
    Caicedo A et al (2005) Photoreceptor synapses degenerate early in experimental choroidal neovascularization. J Comp Neurol 483(3):263–277PubMedCrossRefGoogle Scholar
  98. 98.
    Caicedo A et al (2005) Blood-derived macrophages infiltrate the retina and activate Muller glial cells under experimental choroidal neovascularization. Exp Eye Res 81(1):38–47PubMedCrossRefGoogle Scholar
  99. 99.
    Grossniklaus HE et al (2002) Macrophage and retinal pigment epithelium expression of angiogenic cytokines in choroidal neovascularization. Mol Vis 8:119–126PubMedGoogle Scholar
  100. 100.
    Cao X et al (2011) Macrophage polarization in the maculae of age-related macular degeneration: a pilot study. Pathol Int 61(9):528–535PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Gupta N, Brown KE, Milam AH (2003) Activated microglia in human retinitis pigmentosa, late-onset retinal degeneration, and age-related macular degeneration. Exp Eye Res 76(4):463–471PubMedCrossRefGoogle Scholar
  102. 102.
    Penfold PL et al (1995) Exudative macular degeneration and intravitreal triamcinolone. A pilot study. Aust N Z J Ophthalmol 23(4):293–298PubMedCrossRefGoogle Scholar
  103. 103.
    Cherepanoff S et al (2010) Bruch’s membrane and choroidal macrophages in early and advanced age-related macular degeneration. Br J Ophthalmol 94(7):918–925PubMedCrossRefGoogle Scholar
  104. 104.
    Fritsche LG et al (2013) Seven new loci associated with age-related macular degeneration. Nat Genet 45(4):433–439PubMedCrossRefGoogle Scholar
  105. 105.
    Lim LS et al (2012) Age-related macular degeneration. Lancet 379(9827):1728–1738PubMedCrossRefGoogle Scholar
  106. 106.
    Liu MM, Chan CC, Tuo J (2012) Genetic mechanisms and age-related macular degeneration: common variants, rare variants, copy number variations, epigenetics, and mitochondrial genetics. Hum Genomics 6:13PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    Fisher SA et al (2005) Meta-analysis of genome scans of age-related macular degeneration. Hum Mol Genet 14(15):2257–2264PubMedCrossRefGoogle Scholar
  108. 108.
    Edwards AO et al (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308(5720):421–424PubMedCrossRefGoogle Scholar
  109. 109.
    Hageman GS et al (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 102(20):7227–7232PubMedCentralPubMedCrossRefGoogle Scholar
  110. 110.
    Haines JL et al (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308(5720):419–421PubMedCrossRefGoogle Scholar
  111. 111.
    Klein RJ et al (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308(5720):385–389PubMedCentralPubMedCrossRefGoogle Scholar
  112. 112.
    Gold B et al (2006) Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 38(4):458–462PubMedCentralPubMedCrossRefGoogle Scholar
  113. 113.
    Maller J et al (2006) Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet 38(9):1055–1059PubMedCrossRefGoogle Scholar
  114. 114.
    Yates JR et al (2007) Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 357(6):553–561PubMedCrossRefGoogle Scholar
  115. 115.
    Fagerness JA et al (2009) Variation near complement factor I is associated with risk of advanced AMD. Eur J Hum Genet 17(1):100–104PubMedCentralPubMedCrossRefGoogle Scholar
  116. 116.
    Dewan A et al (2006) HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314(5801):989–992PubMedCrossRefGoogle Scholar
  117. 117.
    Jakobsdottir J et al (2005) Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet 77(3):389–407PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Canfield AE et al (2007) HtrA1: a novel regulator of physiological and pathological matrix mineralization? Biochem Soc Trans 35(Pt 4):669–671PubMedGoogle Scholar
  119. 119.
    Jones A et al (2011) Increased expression of multifunctional serine protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal vasculopathy in mice. Proc Natl Acad Sci USA 108(35):14578–14583PubMedCentralPubMedCrossRefGoogle Scholar
  120. 120.
    Neale BM et al (2010) Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci USA 107(16):7395–7400PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Yu Y et al (2011) Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. Hum Mol Genet 20(18):3699–3709PubMedCentralPubMedCrossRefGoogle Scholar
  122. 122.
    Arakawa S et al (2011) Genome-wide association study identifies two susceptibility loci for exudative age-related macular degeneration in the Japanese population. Nat Genet 43(10):1001–1004PubMedCrossRefGoogle Scholar
  123. 123.
    Raychaudhuri S et al (2011) A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nat Genet 43(12):1232–1236PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Seddon JM et al (2007) Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. JAMA 297(16):1793–1800PubMedCrossRefGoogle Scholar
  125. 125.
    Yu Y et al (2012) Prospective assessment of genetic effects on progression to different stages of age-related macular degeneration using multistate Markov models. Invest Ophthalmol Vis Sci 53(3):1548–1556PubMedCentralPubMedCrossRefGoogle Scholar
  126. 126.
    Seddon JM, Reynolds R, Rosner B (2009) Peripheral retinal drusen and reticular pigment: association with CFHY402H and CFHrs1410996 genotypes in family and twin studies. Invest Ophthalmol Vis Sci 50(2):586–591PubMedCrossRefGoogle Scholar
  127. 127.
    Boulton M, Marshall J, Wong HC (1986) The generation of dense granules within cultured human retinal pigment epithelial cells at senescence. Graefes Arch Clin Exp Ophthalmol 224(2):106–109PubMedCrossRefGoogle Scholar
  128. 128.
    Feeney-Burns L, Berman ER, Rothman H (1980) Lipofuscin of human retinal pigment epithelium. Am J Ophthalmol 90(6):783–791PubMedCrossRefGoogle Scholar
  129. 129.
    Holz FG et al (1994) Analysis of lipid deposits extracted from human macular and peripheral Bruch’s membrane. Arch Ophthalmol 112(3):402–406PubMedCrossRefGoogle Scholar
  130. 130.
    Bookout AL et al (2006) Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 126(4):789–799PubMedCrossRefGoogle Scholar
  131. 131.
    Chawla A et al (2001) Nuclear receptors and lipid physiology: opening the X-files. Science 294(5548):1866–1870PubMedCrossRefGoogle Scholar
  132. 132.
    Germain P et al (2006) Overview of nomenclature of nuclear receptors. Pharmacol Rev 58(4):685–704PubMedCrossRefGoogle Scholar
  133. 133.
    McKenna NJ, O’Malley BW (2002) Minireview: nuclear receptor coactivators–an update. Endocrinology 143(7):2461–2465PubMedGoogle Scholar
  134. 134.
    Aarnisalo P et al (2002) Defining requirements for heterodimerization between the retinoid X receptor and the orphan nuclear receptor Nurr1. J Biol Chem 277(38):35118–35123PubMedCrossRefGoogle Scholar
  135. 135.
    Desvergne B, Michalik L, Wahli W (2006) Transcriptional regulation of metabolism. Physiol Rev 86(2):465–514PubMedCrossRefGoogle Scholar
  136. 136.
    Mangelsdorf DJ et al (1995) The nuclear receptor superfamily: the second decade. Cell 83(6):835–839PubMedCrossRefGoogle Scholar
  137. 137.
    Kurakula K et al (2013) Nuclear receptors in atherosclerosis: a superfamily with many ‘Goodfellas’. Mol Cell Endocrinol 368(1–2):71–84PubMedCrossRefGoogle Scholar
  138. 138.
    Ebrahimi KB, Handa JT (2011) Lipids, lipoproteins, and age-related macular degeneration. J Lipids 2011:802059PubMedCentralPubMedCrossRefGoogle Scholar
  139. 139.
    Ng EW, Adamis AP (2005) Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration. Can J Ophthalmol 40(3):352–368PubMedCrossRefGoogle Scholar
  140. 140.
    Nita M et al (2014) Age-related macular degeneration and changes in the extracellular matrix. Med Sci Monit 20:1003–1016PubMedCentralPubMedCrossRefGoogle Scholar
  141. 141.
    Telander DG (2011) Inflammation and age-related macular degeneration (AMD). Semin Ophthalmol 26(3):192–197PubMedCrossRefGoogle Scholar
  142. 142.
    Rodriguez-Boulan E, Nelson WJ (1989) Morphogenesis of the polarized epithelial cell phenotype. Science 245(4919):718–725PubMedCrossRefGoogle Scholar
  143. 143.
    Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85(3):845–881PubMedCrossRefGoogle Scholar
  144. 144.
    Streilein JW et al (2002) Ocular immune privilege and the impact of intraocular inflammation. DNA Cell Biol 21(5–6):453–459PubMedCrossRefGoogle Scholar
  145. 145.
    He S et al (1994) Dexamethasone induced proliferation of cultured retinal pigment epithelial cells. Curr Eye Res 13(4):257–261PubMedCrossRefGoogle Scholar
  146. 146.
    Ayalasomayajula SP, Ashton P, Kompella UB (2009) Fluocinolone inhibits VEGF expression via glucocorticoid receptor in human retinal pigment epithelial (ARPE-19) cells and TNF-alpha-induced angiogenesis in chick chorioallantoic membrane (CAM). J Ocul Pharmacol Ther 25(2):97–103PubMedCrossRefGoogle Scholar
  147. 147.
    Elliot S et al (2008) Subtype specific estrogen receptor action protects against changes in MMP-2 activation in mouse retinal pigmented epithelial cells. Exp Eye Res 86(4):653–660PubMedCentralPubMedCrossRefGoogle Scholar
  148. 148.
    Marin-Castano ME et al (2003) Regulation of estrogen receptors and MMP-2 expression by estrogens in human retinal pigment epithelium. Invest Ophthalmol Vis Sci 44(1):50–59PubMedCrossRefGoogle Scholar
  149. 149.
    Dwyer MA et al (2011) Research resource: nuclear receptor atlas of human retinal pigment epithelial cells: potential relevance to age-related macular degeneration. Mol Endocrinol 25(2):360–372PubMedCentralPubMedCrossRefGoogle Scholar
  150. 150.
    Malek G et al (2010) PPAR nuclear receptors and altered RPE lipid metabolism in age-related macular degeneration. Adv Exp Med Biol 664:429–436PubMedCrossRefGoogle Scholar
  151. 151.
    Ershov AV, Bazan NG (2000) Photoreceptor phagocytosis selectively activates PPARgamma expression in retinal pigment epithelial cells. J Neurosci Res 60(3):328–337PubMedCrossRefGoogle Scholar
  152. 152.
    Herzlich AA et al (2009) Peroxisome proliferator-activated receptor expression in murine models and humans with age-related macular degeneration. Open Biol J 2:141–148PubMedCentralPubMedCrossRefGoogle Scholar
  153. 153.
    Hatanaka H et al (2012) Epithelial-mesenchymal transition-like phenotypic changes of retinal pigment epithelium induced by TGF-beta are prevented by PPAR-gamma agonists. Invest Ophthalmol Vis Sci 53(11):6955–6963PubMedCrossRefGoogle Scholar
  154. 154.
    Rodrigues GA et al (2011) Differential effects of PPARgamma ligands on oxidative stress-induced death of retinal pigmented epithelial cells. Invest Ophthalmol Vis Sci 52(2):890–903PubMedCrossRefGoogle Scholar
  155. 155.
    Dunn KC et al (1996) ARPE-19, a human retinal pigment epithelial cell line with differentiated properties. Exp Eye Res 62(2):155–169PubMedCrossRefGoogle Scholar
  156. 156.
    Bosch E, Horwitz J, Bok D (1993) Phagocytosis of outer segments by retinal pigment epithelium: phagosome-lysosome interaction. J Histochem Cytochem 41(2):253–263PubMedCrossRefGoogle Scholar
  157. 157.
    Klein BE, Klein R, Lee KE (2000) Reproductive exposures, incident age-related cataracts, and age-related maculopathy in women: the beaver dam eye study. Am J Ophthalmol 130(3):322–326PubMedCrossRefGoogle Scholar
  158. 158.
    Feskanich D et al (2008) Menopausal and reproductive factors and risk of age-related macular degeneration. Arch Ophthalmol 126(4):519–524PubMedCrossRefGoogle Scholar
  159. 159.
    Boekhoorn SS et al (2007) Estrogen receptor alpha gene polymorphisms associated with incident aging macula disorder. Invest Ophthalmol Vis Sci 48(3):1012–1017PubMedCrossRefGoogle Scholar
  160. 160.
    Seitzman RL et al (2008) Estrogen receptor alpha and matrix metalloproteinase 2 polymorphisms and age-related maculopathy in older women. Am J Epidemiol 167(10):1217–1225PubMedCrossRefGoogle Scholar
  161. 161.
    Giddabasappa A et al (2010) 17-beta estradiol protects ARPE-19 cells from oxidative stress through estrogen receptor-beta. Invest Ophthalmol Vis Sci 51(10):5278–5287PubMedCrossRefGoogle Scholar
  162. 162.
    Silveira AC et al (2010) Convergence of linkage, gene expression and association data demonstrates the influence of the RAR-related orphan receptor alpha (RORA) gene on neovascular AMD: a systems biology based approach. Vision Res 50(7):698–715PubMedCentralPubMedCrossRefGoogle Scholar
  163. 163.
    Esfandiary H et al (2005) Association study of detoxification genes in age related macular degeneration. Br J Ophthalmol 89(4):470–474PubMedCentralPubMedCrossRefGoogle Scholar
  164. 164.
    Hu P et al (2013) Aryl hydrocarbon receptor deficiency causes dysregulated cellular matrix metabolism and age-related macular degeneration-like pathology. Proc Natl Acad Sci USA 110(43):E4069–E4078PubMedCentralPubMedCrossRefGoogle Scholar
  165. 165.
    Chang JY, Bora PS, Bora NS (2008) Prevention of oxidative stress-induced retinal pigment epithelial cell death by the PPARgamma agonists, 15-deoxy-delta 12, 14-prostaglandin J(2). PPAR Res 2008:720163PubMedCentralPubMedCrossRefGoogle Scholar
  166. 166.
    Herzlich AA, Tuo J, Chan CC (2008) Peroxisome proliferator-activated receptor and age-related macular degeneration. PPAR Res 2008:389507PubMedCentralPubMedCrossRefGoogle Scholar
  167. 167.
    Malchiodi-Albedi F et al (2008) PPAR-gamma, microglial cells, and ocular inflammation: new venues for potential therapeutic approaches. PPAR Res 2008:295784PubMedCentralPubMedCrossRefGoogle Scholar
  168. 168.
    Qin S, McLaughlin AP, De Vries GW (2006) Protection of RPE cells from oxidative injury by 15-deoxy-delta12,14-prostaglandin J2 by augmenting GSH and activating MAPK. Invest Ophthalmol Vis Sci 47(11):5098–5105PubMedCrossRefGoogle Scholar
  169. 169.
    Willermain F et al (2006) 15-Deoxy-12,14-prostaglandin J2 inhibits interferon gamma induced MHC class II but not class I expression on ARPE cells through a PPAR gamma independent mechanism. Prostaglandins Other Lipid Mediat 80(3–4):136–143PubMedCrossRefGoogle Scholar
  170. 170.
    Lee CH, Olson P, Evans RM (2003) Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology 144(6):2201–2207PubMedCrossRefGoogle Scholar
  171. 171.
    Lee TW et al (2003) Differential expression of inducible nitric oxide synthase and peroxisome proliferator-activated receptor gamma in non-small cell lung carcinoma. Eur J Cancer 39(9):1296–1301PubMedCrossRefGoogle Scholar
  172. 172.
    Pascual G et al (2005) A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 437(7059):759–763PubMedCentralPubMedCrossRefGoogle Scholar
  173. 173.
    Ricote M et al (1998) The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391(6662):79–82PubMedCrossRefGoogle Scholar
  174. 174.
    Mukundan L et al (2009) PPAR-delta senses and orchestrates clearance of apoptotic cells to promote tolerance. Nat Med 15(11):1266–1272PubMedCentralPubMedCrossRefGoogle Scholar
  175. 175.
    Cheng HC et al (2008) Troglitazone suppresses transforming growth factor beta-mediated fibrogenesis in retinal pigment epithelial cells. Mol Vis 14:95–104PubMedCentralPubMedGoogle Scholar
  176. 176.
    Murata T et al (2000) Peroxisome proliferator-activated receptor-gamma ligands inhibit choroidal neovascularization. Invest Ophthalmol Vis Sci 41(8):2309–2317PubMedGoogle Scholar
  177. 177.
    Nagai N et al (2006) Angiotensin II type 1 receptor-mediated inflammation is required for choroidal neovascularization. Arterioscler Thromb Vasc Biol 26(10):2252–2259PubMedCrossRefGoogle Scholar
  178. 178.
    Cameron B, Landreth GE (2010) Inflammation, microglia, and Alzheimer’s disease. Neurobiol Dis 37(3):503–509PubMedCentralPubMedCrossRefGoogle Scholar
  179. 179.
    Mandrekar-Colucci S, Landreth GE (2010) Microglia and inflammation in Alzheimer’s disease. CNS Neurol Disord: Drug Targets 9(2):156–167CrossRefGoogle Scholar
  180. 180.
    Curcio CA et al (2011) The oil spill in ageing Bruch membrane. Br J Ophthalmol 95(12):1638–1645PubMedCentralPubMedCrossRefGoogle Scholar
  181. 181.
    Pikuleva IA, Curcio CA (2014) Cholesterol in the retina: the best is yet to come. Prog Retin Eye Res 41:64–89PubMedCrossRefGoogle Scholar
  182. 182.
    Sene A et al (2013) Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration. Cell Metab 17(4):549–561PubMedCentralPubMedCrossRefGoogle Scholar
  183. 183.
    Wang L et al (2002) Liver X receptors in the central nervous system: from lipid homeostasis to neuronal degeneration. Proc Natl Acad Sci USA 99(21):13878–13883PubMedCentralPubMedCrossRefGoogle Scholar
  184. 184.
    Zheng W et al (2012) Spatial distribution of the pathways of cholesterol homeostasis in human retina. PLoS ONE 7(5):e37926PubMedCentralPubMedCrossRefGoogle Scholar
  185. 185.
    Calkin AC, Tontonoz P (2010) Liver x receptor signaling pathways and atherosclerosis. Arterioscler Thromb Vasc Biol 30(8):1513–1518PubMedCrossRefGoogle Scholar
  186. 186.
    Cramer PE et al (2012) ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335(6075):1503–1506PubMedCentralPubMedCrossRefGoogle Scholar
  187. 187.
    Crunkhorn S (2012) Neurodegenerative disease: RXR agonist reverses Alzheimer’s disease. Nat Rev Drug Discov 11(4):271PubMedCrossRefGoogle Scholar
  188. 188.
    Jiang Q et al (2008) ApoE promotes the proteolytic degradation of Abeta. Neuron 58(5):681–693PubMedCentralPubMedCrossRefGoogle Scholar
  189. 189.
    Zelcer N et al (2007) Attenuation of neuroinflammation and Alzheimer’s disease pathology by liver x receptors. Proc Natl Acad Sci USA 104(25):10601–10606PubMedCentralPubMedCrossRefGoogle Scholar
  190. 190.
    Koldamova R, Lefterov I (2007) Role of LXR and ABCA1 in the pathogenesis of Alzheimer’s disease-implications for a new therapeutic approach. Curr Alzheimer Res 4(2):171–178PubMedCrossRefGoogle Scholar
  191. 191.
    Lakkaraju A, Finnemann SC, Rodriguez-Boulan E (2007) The lipofuscin fluorophore A2E perturbs cholesterol metabolism in retinal pigment epithelial cells. Proc Natl Acad Sci USA 104(26):11026–11031PubMedCentralPubMedCrossRefGoogle Scholar
  192. 192.
    Omarova S et al (2012) Abnormal vascularization in mouse retina with dysregulated retinal cholesterol homeostasis. J Clin Invest 122(8):3012–3023PubMedCentralPubMedCrossRefGoogle Scholar
  193. 193.
    Iriyama A et al (2008) A2E, a pigment of the lipofuscin of retinal pigment epithelial cells, is an endogenous ligand for retinoic acid receptor. J Biol Chem 283(18):11947–11953PubMedCrossRefGoogle Scholar
  194. 194.
    Kim SR et al (2007) The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model. Proc Natl Acad Sci USA 104(49):19273–19278PubMedCentralPubMedCrossRefGoogle Scholar
  195. 195.
    Frank RN et al (1996) Basic fibroblast growth factor and vascular endothelial growth factor are present in epiretinal and choroidal neovascular membranes. Am J Ophthalmol 122(3):393–403PubMedCrossRefGoogle Scholar
  196. 196.
    Lopez PF et al (1996) Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest Ophthalmol Vis Sci 37(5):855–868PubMedGoogle Scholar
  197. 197.
    Zhao B et al (2006) VEGF-A regulates the expression of VEGF-C in human retinal pigment epithelial cells. Br J Ophthalmol 90(8):1052–1059PubMedCentralPubMedCrossRefGoogle Scholar
  198. 198.
    Vandevyver S et al (2013) New insights into the anti-inflammatory mechanisms of glucocorticoids: an emerging role for glucocorticoid-receptor-mediated transactivation. Endocrinology 154(3):993–1007PubMedCrossRefGoogle Scholar
  199. 199.
    Lin FJ et al (2011) Coup d’Etat: an orphan takes control. Endocr Rev 32(3):404–421PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2014

Authors and Affiliations

  1. 1.Department of OphthalmologyDuke University School of MedicineDurhamUSA
  2. 2.Department of PathologyDuke University School of MedicineDurhamUSA

Personalised recommendations