title: RAGE mediated intracellular Aβ uptake contributes to the breakdown of tight junction in retinal pigment epithelium.
abstract: Intracellular amyloid beta (Aβ) has been implicated in neuronal cell death in Alzheimer's disease (AD). Intracellular Aβ also contributes to tight junction breakdown of retinal pigment epithelium (RPE) in age-related macular degeneration (AMD). Although Aβ is predominantly secreted from neuronal cells, the mechanism of Aβ transport into RPE remains to be fully elucidated. In this study, we demonstrated that intracellular Aβ was found concomitantly with the breakdown of tight junction in RPE after subretinal injection of Aβ into the mouse eye. We also presented evidence that receptor for advanced glycation end products (RAGE) contributed to endocytosis of Aβ in RPE. siRNA-mediated knockdown of RAGE prevented intracellular Aβ accumulation as well as subsequent tight junction breakdown in RPE. In addition, we found that RAGE-mediated p38 MAPK signaling contributed to endocytosis of Aβ. Blockade of RAGE/p38 MAPK signaling inhibited Aβ endocytosis, thereby preventing tight junction breakdown in RPE. These results implicate that intracellular Aβ contributes to the breakdown of tight junction in RPE via the RAGE/p38 MAPK-mediated endocytosis. Thus, we suggest that RAGE could be a potential therapeutic target for intracellular Aβ induced outer BRB breakdown in AMD.
authors.affiliation: Fight Against Angiogenesis-Related Blindness Laboratory, Biomedical Research Institute, Seoul National University Hospital, Jongno-gu, Seoul, Korea.|Department of Biomedical Sciences, College of Medicine, Seoul National University, Daehak-ro, Jongno-gu, Seoul, Korea.
authors.forename: Sung Wook
authors.initials: SW
authors.lastname: Park
authors.affiliation: Fight Against Angiogenesis-Related Blindness Laboratory, Biomedical Research Institute, Seoul National University Hospital, Jongno-gu, Seoul, Korea.
authors.forename: Jin Hyoung
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, Life Sciences Concentration GIST (Gwangju Institute of Science and Technology), Cheomdan-gwagiro, Buk-gu, Gwangju, Korea.
authors.forename: Sang Min
authors.initials: SM
authors.lastname: Park
authors.affiliation: Department of Biochemistry, College of Medicine, Konyang University, Seo-gu, Daejeon, Korea.
authors.forename: Minho
authors.initials: M
authors.lastname: Moon
authors.affiliation: Department of Ophthalmology, Ajou University School of Medicine, Yeongtong-gu, Suwon-si, Gyeonggi-do, Korea.
authors.forename: Ki Hwang
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Ophthalmology, College of Medicine, Seoul National University, Daehak-ro, Jongno-gu, Seoul, Korea.|Department of Ophthalmology, Seoul National University Bundang Hospital, Bundang-gu, Seongnam, Gyeonggi-do, Korea.
authors.forename: Kyu Hyung
authors.initials: KH
authors.lastname: Park
authors.affiliation: Department of Life Sciences, Life Sciences Concentration GIST (Gwangju Institute of Science and Technology), Cheomdan-gwagiro, Buk-gu, Gwangju, Korea.
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Park
authors.affiliation: Fight Against Angiogenesis-Related Blindness Laboratory, Biomedical Research Institute, Seoul National University Hospital, Jongno-gu, Seoul, Korea.|Department of Biomedical Sciences, College of Medicine, Seoul National University, Daehak-ro, Jongno-gu, Seoul, Korea.|Department of Ophthalmology, College of Medicine, Seoul National University, Daehak-ro, Jongno-gu, Seoul, Korea.
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D020935:MAP Kinase Signaling System; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000067759:Receptor for Advanced Glycation End Products / Q000097:blood / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D019108:Tight Junctions / Q000378:metabolism* / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D000067759:Receptor for Advanced Glycation End Products
keywords: Gerotarget; age-related macular degeneration; amyloid β; endocytosis; receptor for advanced glycation end products; tight junction