Ceruloplasmin/hephaestin knockout mice model morphologic and molecular features of AMD

Majda Hadziahmetovic, Tzvete Dentchev, Ying Song, Nadine Haddad, Xining He, Paul Hahn, Domenico Pratico, Rong Wen, Z. Leah Harris, John D. Lambris, John Beard, Joshua L. Dunaief

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

PURPOSE. Iron is an essential element in human metabolism but also is a potent generator of oxidative damage with levels that increase with age. Several studies suggest that iron accumulation may be a factor in age-related macular degeneration (AMD). In prior studies, both iron overload and features of AMD were identified in mice deficient in the ferroxidase ceruloplasmin (Cp) and its homologue hephaestin (Heph) (double knockout, DKO). In this study, the location and timing of iron accumulation, the rate and reproducibility of retinal degeneration, and the roles of oxidative stress and complement activation were determined. METHODS. Morphologic analysis and histochemical iron detection by Perls' staining was performed on retina sections from DKO and control mice. Immunofluorescence and immunohistochemistry were performed with antibodies detecting activated complement factor C3, transferrin receptor, L-ferritin, and macrophages. Tissue iron levels were measured by atomic absorption spectrophotometry. Isoprostane F2α-VI, a specific marker of oxidative stress, was quantified in the tissue by gas chromatography/mass spectrometry. RESULTS. DKOs exhibited highly reproducible age-dependent iron overload, which plateaued at 6 months of age, with subsequent progressive retinal degeneration continuing to at least 12 months. The degeneration shared some features of AMD, including RPE hypertrophy and hyperplasia, photoreceptor degeneration, subretinal neovascularization, RPE lipofuscin accumulation, oxidative stress, and complement activation. CONCLUSIONS. DKOs have age-dependent iron accumulation followed by retinal degeneration modeling some of the morphologic and molecular features of AMD. Therefore, these mice are a good platform on which to test therapeutic agents for AMD, such as antioxidants, iron chelators, and antiangiogenic agents.

Original languageEnglish (US)
Pages (from-to)2728-2736
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume49
Issue number6
DOIs
StatePublished - Jun 2008

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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