Differential and Altered Spatial Distribution of Complement Expression in Age-Related Macular Degeneration.

Area of Science:

• Ophthalmology
• Immunology
• Genetics

Background:

• Age-related macular degeneration (AMD) pathogenesis involves complement pathway dysregulation.
• The role of locally synthesized complement components in AMD requires further investigation.

Purpose of the Study:

• To profile complement expression in postmortem eyes with and without AMD.
• To determine if locally synthesized complement components contribute to AMD.

Main Methods:

• Analysis of postmortem fundus images and histological sections to grade AMD severity.
• TaqMan and RNAscope/in situ hybridization to detect complement mRNA.
• Meso scale discovery assay and Western blot to measure complement protein levels.

Main Results:

• Complement mRNA and protein levels were significantly higher (15- to 100-fold) in macular retinal pigment epithelium (RPE)/choroid compared to neural retina.
• Modest elevations in complement mRNA and protein were observed in vitreous and neural retina of eyes with geographic atrophy (GA), but not early/intermediate AMD.
• Complement mRNAs (C3, CFB, CFH, CFI, C1QA) were prominent in GA areas, with C3 mRNA found in microglia/macrophages.

Conclusions:

• The RPE/choroid is the primary ocular site for complement, making it a key target for GA and earlier AMD treatment strategies.
• Local production of complement mRNA in the outer retina and increased complement activation are characteristic of GA.