Research pointing to role of retinal iron overload in AMD

Speaking at the annual meeting of the Association for Research in Vision and Ophthalmology, Dr. Dunaief reported results from studies showing abnormal accumulation of iron, consisting in part of a chelatable pool, in the retinal pigment epithelium (RPE) and Bruch's membrane of maculae from postmortem AMD specimens.

While Dr. Dunaief acknowledged the elevated iron levels could be a consequence of AMD rather than play a causal role, evidence that iron overload can lead to AMD is derived from preclinical experiments. These showed that genetically engineered mice deficient in the iron transport genes ceruloplasmin and hephaestin develop RPE iron overload and retinal features characteristic of AMD.

Iron neurotoxicity Interest in investigating the role of iron overload in AMD derives from several other observations regarding iron neurotoxicity. Dr. Dunaief explained that iron is present in increased levels in the brains of patients with other age-associated neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Furthermore, genetic disorders of iron metabolism dysregulation, including aceruloplasminemia, Friedreich's ataxia, and pantothenate kinase-associated neurodegeneration, are associated with retinal degeneration. In addition, acute iron overload in the retina-coincident with the introduction of an iron foreign body-leads to the development of photoreceptor and RPE degeneration.

Results from the studies evaluating iron levels in human maculae specimens have been published [Arch Ophthalmol 2003; 121:1099-1105]. In those investigations, Dr. Dunaief and colleagues used computer-assisted analysis to quantify Perls Prussian blue staining in 10 postmortem AMD maculae and nine age-matched controls. They found iron levels were significantly increased in the RPE and Bruch's membrane of the AMD specimens compared with the controls. In the AMD subgroup, iron was present in pathologic tissue of specimens from eyes with drusen only, geographic atrophy, and exudative AMD, but was also occasionally detected in healthy tissue. Pretreatment of the tissues with the iron chelator deferroxamine prior to staining reduced the stain signal by about 50%, Dr. Dunaief reported.

Further studies were conducted to investigate the mechanisms of iron homeostasis in the retina and focused on localizing and quantifying the iron storage protein ferritin, the iron transporter ferroportin, and the ferroxidases ceruloplasmin and hephaestin. In tissue from normal mice, ferritin, ferroportin, and the ferroxidases were found in the RPE and various layers of the neural retina.

Regulation of iron metabolism "These findings are important because they suggest the retina tightly regulates iron metabolism and that ferroportin and the ferroxidases cooperate in exporting iron from the RPE," Dr. Dunaief said.

Dr. Dunaief emphasizes that while his lab's work suggests a role for iron in AMD, this has not been proven.OT