Retinal pigment epithelial expression of complement regulator CD46 is altered early in the course of geographic atrophy

• Published in: Experimental eye research Vol. 93; no. 4; pp. 413 - 423
• Main Authors: Vogt, Susan D., Curcio, Christine A., Wang, Lan, Li, Chuan-Ming, McGwin, Gerald, Medeiros, Nancy E., Philp, Nancy J., Kimble, James A., Read, Russell W.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2011
• Subjects: Age; age-related macular degeneration; Aged; Aged, 80 and over; Aging; Atrophy; Calcification; Calcium; CD46; CD46 antigen; complement; Degeneration; Deposits; Eye; ezrin; Female; geographic atrophy; Geographic Atrophy - metabolism; Geographic Atrophy - pathology; histopathology; human; Humans; Immunoenzyme Techniques; immunohistochemistry; Immunoreactivity; inflammation; Macular degeneration; Male; membrane cofactor protein; Membrane Cofactor Protein - metabolism; Monocarboxylic Acid Transporters - metabolism; Photoreceptors; Polarity; Protein transport; Retina; retinal pigment epithelium; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - pathology; Therapeutic applications; Tissue Donors; geographic atrophy; inflammation; histopathology; immunohistochemistry; complement; CD46; age-related macular degeneration; human
• ISSN: 0014-4835; 1096-0007
• DOI: 10.1016/j.exer.2011.06.002

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. ► We examine expression of complement regulator CD46 on the RPE in geographic atrophy. ► CD46 expression is compared to control polarized proteins MCT3 and ezrin. ► CD46 expression is altered at the earliest stage of geographic atrophy. ► This alteration occurs before clinically detectable changes are evident.