Generation of dual mouse models of retinal degeneration with slow and rapid progression driven by ectopic RIP3...

Dry age-related macular degeneration (AMD) is a leading cause of blindness, characterized by progressive loss of retinal pigment epithelium (RPE) and subsequent photoreceptor degeneration. Current experimental models, including sodium iodate-induced injury, fail to fully recapitulate the chronic, age-related progression of the human disease. Although RIP3-mediated necroptosis has been strongly implicated in RPE cell death, its direct contribution to retinal degeneration in vivo remains unclear. To address this limitation, we generated two RIP3 transgenic mouse lines with distinct patterns of RIP3 overexpression. While RIP3-Tg mice exhibit systemic RIP3 overexpression, RIP3-Tg-RPE mice display additional RPE-specific overexpression beyond the levels observed in RIP3-Tg mice. We then evaluated these transgenic lines, along with wild-type controls, for age-driven retinal degeneration by using optical coherence tomography (OCT), behavior-based visual function assays, and molecular profiling of inflammation and cell death. First, RIP3-Tg mice exhibited gradual retinal thinning, progressive visual decline, and sustained upregulation of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) over 6-15 months, recapitulating the slow progression of dry-AMD. Second, RIP3-Tg-RPE mice, which exhibit further RPE-specific increases in RIP3 expression, showed markedly accelerated retinal degeneration, with significant structural and functional deficits evident as early as 2 months of age. These findings indicate that ectopic RIP3 expression in the RPE contributes to inflammatory responses and subsequent retinal degeneration. Collectively, our results highlight RIP3 as a potential contributing factor in the progression of retinal degeneration and introduce biologically relevant transgenic models that capture both slow and accelerated disease progression. These models provide a valuable platform for investigating disease mechanisms and developing therapeutic strategies targeting necroptosis in dry-AMD.