Retinal pigment epithelial expression of complement regulator CD46 is altered early in the course of geographic atrophy
Open accessAbstract
In geographic atrophy (GA), the non-neovascular end stage of age-related macular degeneration (AMD), the macular retinal pigment epithelium (RPE) progressively degenerates. Membrane cofactor protein (MCP, CD46) is the only membrane-bound regulator of complement expressed on the human RPE basolateral surface. Based on evidence of the role of complement in AMD, we hypothesized that altered CD46 expression on the RPE would be associated with GA development and/or progression. Here we report the timeline of CD46 protein expression changes across the GA transition zone, relative to control eyes, and relative to events in other chorioretinal layers. Eleven donor eyes (mean age 87.0 ± 4.1 yr) with GA and 5 control eyes (mean age 84.0 ± 8.9 yr) without GA were evaluated. Macular cryosections were stained with PASH for basal deposits, von Kossa for calcium, and for CD46 immunoreactivity. Internal controls for protein expression were provided by an independent basolateral protein, monocarboxylate transporter 3 (MCT3) and an apical protein, ezrin. Within zones defined by 8 different semi-quantitative grades of RPE morphology, we determined the location and intensity of immunoreactivity, outer segment length, and Bruch's membrane calcification. Differences between GA and control eyes and between milder and more severe RPE stages in GA eyes were assessed statistically. Increasing grades of RPE degeneration were associated with progressive loss of polarity and loss of intensity of staining of CD46, beginning with the stages that are considered normal aging (grades 0-1). Those GA stages with affected CD46 immunoreactivity exhibited basal laminar deposit, still-normal photoreceptors, and concomitant changes in control protein expression. Activated or anteriorly migrated RPE (grades 2-3) exhibited greatly diminished CD46. Changes in RPE CD46 expression thus occur early in GA, before there is evidence of morphological RPE change. At later stages of degeneration, CD46 alterations occur within a context of altered RPE polarity. These changes precede degeneration of the overlying retina and suggest that therapeutic interventions be targeted to the RPE.
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Reduced expression of FH and CD46 by RPE cells is observed in AMD, and this coincides with increased deposition of the MAC and cell lysis.
“Reduced expression of FH and CD46 by RPE cells is observed in AMD, and this coincides with increased deposition of the MAC and cell lysis [132,133].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [133]
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Edwards, M., & Lutty, G. A. (2021) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-030-66014-7_4 · Cited by 32 · see citing works
Annamalai, B., Parsons, N., Nicholson, C., Obert, E., Jones, B., & Rohrer, B. (2021) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.62.4.11 · Cited by 16 · see citing works
- Authors
- Vogt, S. D., Curcio, C. A., Wang, L., Li, C.-M., McGwin, G., Medeiros, N. E., Philp, N. J., Kimble, J. A., & Read, R. W.
- Affiliations
- University of Alabama at Birmingham (US)
- Thomas Jefferson University (US)
- Corresponding author
- Read, Russell W.
- Venue
- Experimental Eye Research
- Publisher
- Elsevier BV
- Published
- 2011-10
- Volume
- 93
- Issue
- 4
- Pages
- 413-423
- ISSN
- 0014-4835 (ISSN-L)
- PMC
- PMC3202648
- OpenAlex
- W2080778821
- Cited by
- 104
- References
- 81
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 6 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 6 · 2019: 5 · 2018: 4 · 2017: 7 · 2016: 9 · 2015: 8 · 2014: 12 · 2013: 6 · 2012: 11
- FWCI
- 9.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Experimental Eye Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Eye Institute (EY012042, R01EY012042, R56EY012042, R01EY006109, EY06109)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Keywords
- geographic atrophy, retinal pigment epithelium, CD46, membrane cofactor protein, complement regulation, age-related macular degeneration, RPE degeneration, basal laminar deposits, photoreceptor outer segment length, ezrin
- MeSH terms
- Aged, Aged, 80 and over, Female, Humans, Immunoenzyme Techniques, Male, Tissue Donors, Monocarboxylic Acid Transporters, Symporters, Membrane Cofactor Protein, Retinal Pigment Epithelium, Geographic Atrophy
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