title: Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration.
abstract: 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.
authors.affiliation: Department of Ophthalmology, Duke Eye Center, Duke University, Durham, NC 27710, USA.
authors.forename: Jin-Dong
authors.initials: JD
authors.lastname: Ding
authors.forename: Lincoln V
authors.initials: LV
authors.lastname: Johnson
authors.forename: Rolf
authors.initials: R
authors.lastname: Herrmann
authors.forename: Sina
authors.initials: S
authors.lastname: Farsiu
authors.forename: Stephanie G
authors.initials: SG
authors.lastname: Smith
authors.forename: Marybeth
authors.initials: M
authors.lastname: Groelle
authors.forename: Brian E
authors.initials: BE
authors.lastname: Mace
authors.forename: Patrick
authors.initials: P
authors.lastname: Sullivan
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Jamison
authors.forename: Una
authors.initials: U
authors.lastname: Kelly
authors.forename: Ons
authors.initials: O
authors.lastname: Harrabi
authors.forename: Sangeetha Subbarao
authors.initials: SS
authors.lastname: Bollini
authors.forename: Jeanette
authors.initials: J
authors.lastname: Dilley
authors.forename: Dione
authors.initials: D
authors.lastname: Kobayashi
authors.forename: Bing
authors.initials: B
authors.lastname: Kuang
authors.forename: Wenlin
authors.initials: W
authors.lastname: Li
authors.forename: Jaume
authors.initials: J
authors.lastname: Pons
authors.forename: John C
authors.initials: JC
authors.lastname: Lin
authors.forename: Catherine
authors.initials: C
authors.lastname: Bowes Rickman
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage / Q000627:therapeutic use; D053327:Apolipoprotein E4 / Q000235:genetics; D003165:Complement System Proteins / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008268:Macular Degeneration / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000276:immunology; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology*; D015354:Vision, Low / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D016229:Amyloid beta-Peptides; D018033:Antibodies, Bispecific; D053327:Apolipoprotein E4; D004041:Dietary Fats; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D003165:Complement System Proteins