title: Iron increases APP translation and amyloid-beta production in the retina.
abstract: Age-related macular degeneration (AMD) is the most common cause of blindness among older adults in developed countries, and retinal iron accumulation may exacerbate the disease. Iron can upregulate the production of amyloid precursor protein (APP). Since amyloid-β (Aβ), a byproduct of APP proteolysis, is found in drusen, the histopathological hallmark of AMD, we tested the role of iron in regulating APP and Aβ levels in the retinal pigment epithelial cell line ARPE-19. We found that treatment with ferric ammonium citrate (FAC) increases APP at the translational level. FAC treatment also results in increased generation of APP C-terminal fragments C83 and C99, the products of APP proteolysis by α- and β-secretase, respectively, as well as levels of Aβ42, a highly aggregative amyloid species. Additionally, retinal tissue sections from a patient with aceruloplasminemia, a disease causing iron overload in the retinal pigment epithelium (RPE), showed increased Aβ deposition in the RPE and drusen. Overall, our results suggest that RPE iron overload could contribute to Aβ accumulation in the retina.
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, 305 Stellar-Chance Laboratory, 422 Curie Blvd, Philadelphia, PA 19104, USA. Electronic address: lucieguo@mail.med.upenn.edu.
authors.forename: Lucie Y
authors.initials: LY
authors.lastname: Guo
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, 305 Stellar-Chance Laboratory, 422 Curie Blvd, Philadelphia, PA 19104, USA; Drexel University College of Medicine, 2900 W Queen Ln, Philadelphia, PA 19129, USA. Electronic address: oa43@drexel.edu.
authors.forename: Oleg
authors.initials: O
authors.lastname: Alekseev
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, 305 Stellar-Chance Laboratory, 422 Curie Blvd, Philadelphia, PA 19104, USA. Electronic address: yafengli@mail.med.upenn.edu.
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Li
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, 305 Stellar-Chance Laboratory, 422 Curie Blvd, Philadelphia, PA 19104, USA. Electronic address: yingsong@mail.med.upenn.edu.
authors.forename: Ying
authors.initials: Y
authors.lastname: Song
authors.affiliation: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, 305 Stellar-Chance Laboratory, 422 Curie Blvd, Philadelphia, PA 19104, USA. Electronic address: jdunaief@upenn.edu.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Dunaief
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics*; D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism*; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D012333:RNA, Messenger; D007501:Iron
keywords: Aceruloplasminemia; Age-related macular degeneration; Amyloid precursor protein; Amyloid-beta; Iron