Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 28, Pages E279-E287Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1100901108
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Funding
- Pfizer Inc.
- National Institutes of Health [R24 EY017404, R01 EY019038, P30 EY005722]
- Research to Prevent Blindness, Inc.
- Core Grants to the Duke Eye Center
- RPB Special Scholars Award
- Ruth and Milton Steinbach Fund
- Macular Vision Research Foundation
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Age-related macular degeneration (AMD) is a leading cause of visual dysfunction worldwide. Amyloid beta (A beta) peptides, A beta 1-40 (A beta 40) and A beta 1-42 (A beta 42), have been implicated previously in the AMD disease process. Consistent with a pathogenic role for A beta, 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 A beta-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 A beta 40 and A beta 42. Concomitant reduction in the levels of A beta and activated complement components in sub-RPE deposits and structural preservation of the RPE are associated with anti-A beta 40/42 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-A beta antibodies. They also implicate A beta in the pathogenesis of AMD and identify A beta as a viable therapeutic target for its treatment.
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