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

Jin-Dong Dinga,
Lincoln V. Johnsonb,
Rolf Herrmanna,
Sina Farsiua,
Stephanie G. Smitha,
Marybeth Groellea,
Brian E. Macec,
Patrick Sullivanc,
Jeffrey A. Jamisond,
Una Kellya,
Ons Harrabie,
Sangeetha Subbarao Bollinie,
Jeanette Dilleye,
Dione Kobayashie,
Bing Kuangf,
Wenlin Lif,
Jaume Ponse,
John C. Line,1, and
Catherine Bowes Rickmana,g,1

+ Author Affiliations

aDepartment of Ophthalmology, Duke Eye Center, Duke University, Durham, NC 27710;
bCenter for the Study of Macular Degeneration, Neuroscience Research Institute, University of California, Santa Barbara, CA 93106;
cDivision of Geriatrics, Department of Medicine, Durham Veterans Affairs Hospitals Medical Center, Duke University, Durham, NC 27705;
dOphthy-DS, Inc., MPI Research, Inc., Mattawan, MI 49071;
eRinat, Pfizer Inc., South San Francisco, CA 94080;
fWorldwide Research and Development, Pfizer Inc., La Jolla, CA 92121; and
gDepartment of Cell Biology, Duke University, Durham, NC 27710

Edited by Alan Bird, University of London, London, United Kingdom, and accepted by the Editorial Board May 24, 2011 (received for review January 17, 2011)


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.

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Author contributions: J.-D.D., L.V.J., J.C.L., and C.B.R. designed research; J.-D.D., R.H., S.G.S., M.G., B.E.M., J.A.J., U.K., O.H., S.S.B., J.D., D.K., B.K., W.L., and J.P. performed research; S.F., P.S., and J.C.L. contributed new reagents/analytic tools; J.-D.D., L.V.J., R.H., S.F., S.G.S., J.A.J., U.K., B.K., J.C.L., and C.B.R. analyzed data; and C.B.R. wrote the paper.

Conflict of interest statement: O.H., S.S.B., J.D., D.K., B.K., W.L., J.P., and J.C.L. are full-time employees of Pfizer Inc., and Pfizer Inc. owns the intellectual properties of the antibodies described herein. L.V.J. and C.B.R. have received research funding from Pfizer Inc.

This article is a PNAS Direct Submission.

This article contains supporting information online at

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