Transgenic mice expressing variants of complement factor H develop AMD-like retinal findings

Area of Science:

• Ophthalmology
• Immunology
• Genetics

Background:

• Complement factor H (CFH) regulates the alternative complement pathway.
• A specific CFH variant (Y402H) is a known genetic risk factor for Age-related Macular Degeneration (AMD).

Purpose of the Study:

• To create a pathophysiologically relevant animal model for AMD by incorporating the Y402H CFH genetic risk factor.
• To investigate the role of complement system dysregulation in AMD pathogenesis.

Main Methods:

• Generation of chimeric CFH transgenic mouse lines expressing human CFH SCR6-8 variants (402Y or 402H) with mouse CFH flanking sequences.
• Analysis of transgenic mRNA and protein expression, functionality, and assessment of retinal phenotypes in adult mice.
• Histological and ultrastructural examination of retinal tissues to identify AMD-like changes.

Main Results:

• Transgenic CFH mRNA and functional chimeric proteins were expressed in mice, restoring physiological C3 levels in CFH knockout mice.
• Mice exhibited AMD-like characteristics, including subretinal drusen-like deposits and accumulation of subretinal macrophage/microglia.
• Histology revealed basal laminar deposits, long-spaced collagen, increased lipofuscin, and C3d deposition in the sub-RPE band.

Conclusions:

• The developed chimeric CFH mouse model successfully recapitulates key AMD-like pathological features.
• This model serves as a valuable tool for studying the involvement of the complement system and immune factors in early AMD development.