Skip to main content
SpringerLink
Log in

A2E and lipofuscin distributions in macaque retinal pigment epithelium are similar to human

  • Paper
  • Published:
Photochemical & Photobiological Sciences Aims and scope Submit manuscript

Abstract

The accumulation of lipofuscin, an autofluorescent aging marker, in the retinal pigment epithelium (RPE) has been implicated in the development of age-related macular degeneration (AMD). Lipofuscin contains several visual cycle byproducts, most notably the bisretinoid N-retinylidene-N-retinylethanolamine (A2E). Previous studies with human donor eyes have shown a significant mismatch between lipofuscin autofluorescence (AF) and A2E distributions. The goal of the current project was to examine this relationship in a primate model with a retinal anatomy similar to that of humans. Ophthalmologically naive young (<10 years., N = 3) and old (>10 years., N = 4) Macaca fascicularis (macaque) eyes, were enucleated, dissected to yield RPE/choroid tissue, and flat-mounted on indium-tin-oxide-coated conductive slides. To compare the spatial distributions of lipofuscin and A2E, fluorescence and mass spectrometric imaging were carried out sequentially on the same samples. The distribution of lipofuscin fluorescence in the primate RPE reflected previously obtained human results, having the highest intensities in a perifoveal ring. Contrarily, A2E levels were consistently highest in the periphery, confirming a lack of correlation between the distributions of lipofuscin and A2E previously described in human donor eyes. We conclude that the mismatch between lipofuscin AF and A2E distributions is related to anatomical features specific to primates, such as the macula, and that this primate model has the potential to fill an important gap in current AMD research.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. E. A. Porta, Pigments in aging: an overview, Ann. N. Y. Acad. Sci., 2002, 959, 57–65.

    Article  CAS  PubMed  Google Scholar 

  2. M. Nakano, F. Oenzil, T. Mizuno and S. Gotoh, Age-related changes in the lipofuscin accumulation of brain and heart, Gerontology, 1995, 41Suppl. 2, 69–79.

    Article  CAS  PubMed  Google Scholar 

  3. L. Feeney, Lipofuscin and melanin of human retinal pigment epithelium. Fluorescence, enzyme cytochemical, and ultrastructural studies, Invest. Ophthalmol. Visual Sci., 1978, 17, 583–600.

    CAS  Google Scholar 

  4. G. L. Wing, G. C. Blanchard, J. J. Weiter, The topography and age relationship of lipofuscin concentration in the retinal pigment epithelium, Invest. Ophthalmol. Visual Sci., 1978, 17, 601–607.

    CAS  Google Scholar 

  5. F. C. Delori, C. K. Dorey, G. Staurenghi, O. Arend, D. G. Goger and J. J. Weiter, In vivo fluorescence of the ocular fundus exhibits retinal pigment epithelium lipofuscin characteristics, Invest. Ophthalmol. Visual Sci., 1995, 36, 718–729.

    CAS  Google Scholar 

  6. N. Ulfig, Altered lipofuscin pigmentation in the basal nucleus (Meynert) in Parkinson’s disease, Neurosci. Res., 1989, 6, 456–462.

    Article  CAS  PubMed  Google Scholar 

  7. H. Nakanishi, T. Amano, D. F. Sastradipura, Y. Yoshimine, T. Tsukuba, K. Tanabe, I. Hirotsu, T. Ohono and K. Yamamoto, Increased expression of cathepsins E and D in neurons of the aged rat brain and their colocalization with lipofuscin and carboxy-terminal fragments of Alzheimer amyloid precursor protein, J. Neurochem., 1997, 68, 739–749.

    Article  CAS  PubMed  Google Scholar 

  8. N. P. Bajaj, S. T. Al-Sarraj, V. Anderson, M. Kibble, N. Leigh and C. C. Miller, Cyclin-dependent kinase-5 is associated with lipofuscin in motor neurones in amyotrophic lateral sclerosis, Neurosci. Lett., 1998, 245, 45–48.

    Article  CAS  PubMed  Google Scholar 

  9. B. S. Winkler, M. E. Boulton, J. D. Gottsch and P. Sternberg, Oxidative damage and age-related macular degeneration, Mol. Vision, 1999, 5, 32.

    CAS  Google Scholar 

  10. J. R. Sparrow and M. Boulton, RPE lipofuscin and its role in retinal pathobiology, Exp. Eye Res., 2005, 80, 595–606.

    Article  CAS  PubMed  Google Scholar 

  11. T. R. Burke, T. Duncker, R. L. Woods, J. P. Greenberg, J. Zernant, S. H. Tsang, R. T. Smith, R. Allikmets, J. R. Sparrow and F. C. Delori, Quantitative fundus autofluorescence in recessive Stargardt disease, Invest. Ophthalmol. Visual Sci., 2014, 55, 2841–2852.

    Article  CAS  Google Scholar 

  12. F. C. Delori, G. Staurenghi, O. Arend, C. K. Dorey, D. G. Goger and J. J. Weiter, In vivo measurement of lipofuscin in Stargardt’s disease–Fundus flavimaculatus, Invest. Ophthalmol. Visual Sci., 1995, 36, 2327–2331.

    CAS  Google Scholar 

  13. G. E. Eldred and M. R. Lasky, Retinal age pigments generated by self-assembling lysosomotropic detergents, Nature, 1993, 361, 724–726.

    Article  CAS  PubMed  Google Scholar 

  14. K. P. Ng, B. Gugiu, K. Renganathan, M. W. Davies, X. Gu, J. S. Crabb, S. R. Kim, M. B. Rozanowska, V. L. Bonilha, M. E. Rayborn, R. G. Salomon, J. R. Sparrow, M. E. Boulton, J. G. Hollyfield and J. W. Crabb, Retinal pigment epithelium lipofuscin proteomics, Mol. Cell. Proteomics, 2008, 7, 1397–1405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. J. R. Sparrow, E. Gregory-Roberts, K. Yamamoto, A. Blonska, S. K. Ghosh, K. Ueda and J. Zhou, The bisretinoids of retinal pigment epithelium, Prog. Retinal Eye Res., 2012, 31, 121–135.

    Article  CAS  Google Scholar 

  16. N. Sakai, J. Decatur, K. Nakanishi and G. Eldred, Ocular Age Pigment “A2-E”: An Unprecedented Pyridinium Bisretinoid, J. Am. Chem. Soc., 1996, 118, 1559–1560.

    Article  CAS  Google Scholar 

  17. C. A. Parish, M. Hashimoto, K. Nakanishi, J. Dillon and J. Sparrow, Isolation and one-step preparation of A2E and iso-A2E, fluorophores from human retinal pigment epithelium, Proc. Natl. Acad. Sci. U. S. A., 1998, 95, 14609–14613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. F. Quazi and R. S. Molday, ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11-cis-retinal, Proc. Natl. Acad. Sci. U. S. A., 2014, 111, 5024–5029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. N. P. Boyer, D. Higbee, M. B. Currin, L. R. Blakeley, C. Chen, Z. Ablonczy, R. K. Crouch and Y. Koutalos, Lipofuscin and N-retinylidene-N-retinylethanolamine (A2E) accumulate in retinal pigment epithelium in absence of light exposure: their origin is 11-cis-retinal, J. Biol. Chem., 2012, 287, 22276–22286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. J. Liu, Y. Itagaki, S. Ben-Shabat, K. Nakanishi and J. R. Sparrow, The biosynthesis of A2E, a fluorophore of aging retina, involves the formation of the precursor, A2-PE, in the photoreceptor outer segment membrane, J. Biol. Chem., 2000, 275, 29354–29360.

    Article  CAS  PubMed  Google Scholar 

  21. N. M. Haralampus-Grynaviski, L. E. Lamb, C. M. Clancy, C. Skumatz, J. M. Burke, T. Sarna and J. D. Simon, Spectroscopic and morphological studies of human retinal lipofuscin granules, Proc. Natl. Acad. Sci. U. S. A., 2003, 100, 3179–3184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. T. B. Feldman, M. A. Yakovleva, P. M. Arbukhanova, S. A. Borzenok, A. S. Kononikhin, I. A. Popov, E. N. Nikolaev and M. A. Ostrovsky, Changes in spectral properties and composition of lipofuscin fluorophores from human-retinal-pigment epithelium with age and pathology, Anal. Bioanal. Chem., 2015, 407, 1075–1088.

    Article  CAS  PubMed  Google Scholar 

  23. P. Bhosale, B. Serban and P. S. Bernstein, Retinal carotenoids can attenuate formation of A2E in the retinal pigment epithelium, Arch. Biochem. Biophys., 2009, 483, 175–181.

    Article  CAS  PubMed  Google Scholar 

  24. A. Maeda, M. Golczak, Y. Chen, K. Okano, H. Kohno, S. Shiose, K. Ishikawa, W. Harte, G. Palczewska, T. Maeda and K. Palczewski, Primary amines protect against retinal degeneration in mouse models of retinopathies, Nat. Chem. Biol., 2012, 8, 170–178.

    Article  CAS  Google Scholar 

  25. J. E. Roberts, B. M. Kukielczak, D. N. Hu, D. S. Miller, P. Bilski, R. H. Sik, A. G. Motten and C. F. Chignell, The role of A2E in prevention or enhancement of light damage in human retinal pigment epithelial cells, Photochem. Photobiol., 2002, 75, 184–190.

    Article  CAS  PubMed  Google Scholar 

  26. Z. Ablonczy, N. Smith, D. M. Anderson, A. C. Grey, J. Spraggins, Y. Koutalos, K. L. Schey and R. K. Crouch, The utilization of fluorescence to identify the components of lipofuscin by imaging mass spectrometry, Proteomics, 2014, 14, 936–944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Z. Ablonczy, D. Higbee, A. C. Grey, Y. Koutalos, K. L. Schey and R. K. Crouch, Similar molecules spatially correlate with lipofuscin and N-retinylidene-N-retinylethanolamine in the mouse but not in the human retinal pigment epithelium, Arch. Biochem. Biophys., 2013, 539, 196–202.

    Article  CAS  PubMed  Google Scholar 

  28. Z. Ablonczy, D. Higbee, D. M. Anderson, M. Dahrouj, A. C. Grey, D. Gutierrez, Y. Koutalos, K. L. Schey, A. Hanneken and R. K. Crouch, Lack of correlation between the spatial distribution of A2E and lipofuscin fluorescence in the human retinal pigment epithelium, Invest. Ophthalmol. Visual Sci., 2013, 54, 5535–5542.

    Article  CAS  Google Scholar 

  29. Z. Ablonczy, D. B. Gutierrez, A. C. Grey, K. L. Schey and R. K. Crouch, Molecule-specific imaging and quantitation of A2E in the RPE, Adv. Exp. Med. Biol., 2012, 723, 75–81.

    Article  CAS  PubMed  Google Scholar 

  30. A. C. Grey, R. K. Crouch, Y. Koutalos, K. L. Schey and Z. Ablonczy, Spatial localization of A2E in the retinal pigment epithelium, Invest. Ophthalmol. Visual Sci., 2011, 52, 3926–3933.

    Article  Google Scholar 

  31. K. C. Wikler and P. Rakic, Distribution of photoreceptor subtypes in the retina of diurnal and nocturnal primates, J. Neurosci., 1990, 10, 3390–3401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. C. A. Curcio, K. R. Sloan Jr., O. Packer, A. E. Hendrickson and R. E. Kalina, Distribution of cones in human and monkey retina: individual variability and radial asymmetry, Science, 1987, 236, 579–582.

    Article  CAS  PubMed  Google Scholar 

  33. O. Packer, A. E. Hendrickson and C. A. Curcio, Photoreceptor topography of the retina in the adult pigtail macaque (Macaca nemestrina), J. Comp. Neurol., 1989, 288, 165–183.

    Article  CAS  PubMed  Google Scholar 

  34. K. C. Wikler, R. W. Williams and P. Rakic, Photoreceptor mosaic: number and distribution of rods and cones in the rhesus monkey retina, J. Comp. Neurol., 1990, 297, 499–508.

    Article  CAS  PubMed  Google Scholar 

  35. D. Pascolini, S. P. Mariotti, G. P. Pokharel, R. Pararajasegaram, D. Etya’ale, A. D. Negrel and S. Resnikoff, 2002 global update of available data on visual impairment: a compilation of population-based prevalence studies, Ophthal. Epidemiol., 2004, 11, 67–115.

    Article  CAS  Google Scholar 

  36. J. R. Sparrow, C. A. Parish, M. Hashimoto and K. Nakanishi, A2E, a lipofuscin fluorophore, in human retinal pigmented epithelial cells in culture, Invest. Ophthalmol. Visual Sci., 1999, 40, 2988–2995.

    CAS  Google Scholar 

  37. P. Charbel Issa, A. R. Barnard, M. S. Singh, E. Carter, Z. Jiang, R. A. Radu, U. Schraermeyer and R. E. MacLaren, Fundus autofluorescence in the Abca4(–/–) mouse model of Stargardt disease–correlation with accumulation of A2E, retinal function, and histology, Invest. Ophthalmol. Visual Sci., 2013, 54, 5602–5612.

    Article  CAS  Google Scholar 

  38. T. Ach, E. Tolstik, J. D. Messinger, A. V. Zarubina, R. Heintzmann and C. A. Curcio, Lipofuscin re-distribution and loss accompanied by cytoskeletal stress in retinal pigment epithelium of eyes with age-related macular degeneration, Invest. Ophthalmol. Visual Sci., 2015, 56, 3242–3252.

    Article  CAS  Google Scholar 

  39. R. P. Tornow and R. Stilling, Variation in sensitivity, absorption and density of the central rod distribution with eccentricity, Acta Anatomica, 1998, 162, 163–168.

    Article  CAS  PubMed  Google Scholar 

  40. R. W. Young, The renewal of rod and cone outer segments in the rhesus monkey, J. Cell Biol., 1971, 49, 303–318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. J. J. Hunter, J. I. Morgan, W. H. Merigan, D. H. Sliney, J. R. Sparrow and D. R. Williams, The susceptibility of the retina to photochemical damage from visible light, Prog. Retinal Eye Res., 2012, 31, 28–42.

    Article  Google Scholar 

  42. J. Weng, N. L. Mata, S. M. Azarian, R. T. Tzekov, D. G. Birch and G. H. Travis, Insights into the function of Rim protein in photoreceptors and etiology of Stargardt’s disease from the phenotype in abcr knockout mice, Cell, 1999, 98, 13–23.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, USA

    Patrick Pallitto, Zsolt Ablonczy, Yiannis Koutalos & Rosalie K. Crouch

  2. Department of Cell and Molecular Pharmacology and Experimental Therapeutics and MUSC Proteomics Center, Medical University of South Carolina, Charleston, South Carolina, USA

    E. Ellen Jones & Richard R. Drake

  3. Department of Biological Sciences, Allergan Inc., Irvine, CA, USA

    John Donello & Julia Herrmann

Authors
  1. Patrick Pallitto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zsolt Ablonczy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Ellen Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard R. Drake
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yiannis Koutalos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rosalie K. Crouch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John Donello
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Julia Herrmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zsolt Ablonczy.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pallitto, P., Ablonczy, Z., Jones, E.E. et al. A2E and lipofuscin distributions in macaque retinal pigment epithelium are similar to human. Photochem Photobiol Sci 14, 1888–1895 (2015). https://doi.org/10.1039/c5pp00170f

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1039/c5pp00170f

Search

Navigation