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Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration

2011; National Academy of Sciences; Volume: 108; Issue: 28 Linguagem: Inglês

10.1073/pnas.1100901108

1091-6490

Jindong Ding, Lincoln V. Johnson, Rolf Herrmann, Sina Farsiu, Stephanie G. Smith, Marybeth Groelle, Brian E. Mace, Patrick M. Sullivan, Jeffrey Adam Jamison, Una Kelly, Ons Harrabi, Sangeetha Bollini, Jeanette Dilley, Dione Kobayashi, Bing Kuang, Wenlin Li, Jaume Pons, John Lin, Catherine Bowes Rickman,

Glaucoma and retinal disorders

Age-related macular degeneration (AMD) is a leading cause of visual dysfunction worldwide. Amyloid β (Aβ) peptides, Aβ1–40 (Aβ40) and Aβ1–42 (Aβ42), have been implicated previously in the AMD disease process. Consistent with a pathogenic role for Aβ, we show here that a mouse model of AMD that invokes multiple factors that are known to modify AMD risk (aged human apolipoprotein E 4 targeted replacement mice on a high-fat, cholesterol-enriched diet) presents with Aβ-containing deposits basal to the retinal pigmented epithelium (RPE), histopathologic changes in the RPE, and a deficit in scotopic electroretinographic response, which is reflective of impaired visual function. Strikingly, these electroretinographic deficits are abrogated in a dose-dependent manner by systemic administration of an antibody targeting the C termini of Aβ40 and Aβ42. Concomitant reduction in the levels of Aβ and activated complement components in sub-RPE deposits and structural preservation of the RPE are associated with anti-Aβ40/42 antibody immunotherapy and visual protection. These observations are consistent with the reduction in amyloid plaques and improvement of cognitive function in mouse models of Alzheimer's disease treated with anti-Aβ antibodies. They also implicate Aβ in the pathogenesis of AMD and identify Aβ as a viable therapeutic target for its treatment.