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RAGE mediated intracellular Aβ uptake contributes to the breakdown of tight junction in retinal pigment epithelium

2015; Impact Journals LLC; Volume: 6; Issue: 34 Linguagem: Inglês

10.18632/oncotarget.5894

1949-2553

Sung Wook Park, Jin Hyoung Kim, Sang Min Park, Minho Moon, Kihwang Lee, Kyu Hyung Park, Woo Jin Park, Jeong Hun Kim,

Barrier Structure and Function Studies

// Sung Wook Park 1,2 , Jin Hyoung Kim 1 , Sang Min Park 3 , Minho Moon 4 , Kihwang Lee 5 , Kyu Hyung Park 6,7 , Woo Jin Park 3 and Jeong Hun Kim 1,2,6 1 Fight against Angiogenesis-Related Blindness Laboratory, Biomedical Research Institute, Seoul National University Hospital, Jongno-gu, Seoul, Korea 2 Department of Biomedical Sciences, College of Medicine, Seoul National University, Daehak-ro, Jongno-gu, Seoul, Korea 3 Department of Life Sciences, Life Sciences Concentration GIST (Gwangju Institute of Science and Technology), Cheomdan-gwagiro, Buk-gu, Gwangju, Korea 4 Department of Biochemistry, College of Medicine, Konyang University, Seo-gu, Daejeon, Korea 5 Department of Ophthalmology, Ajou University School of Medicine, Yeongtong-gu, Suwon-si, Gyeonggi-do, Korea 6 Department of Ophthalmology, College of Medicine, Seoul National University, Daehak-ro, Jongno-gu, Seoul, Korea 7 Department of Ophthalmology, Seoul National University Bundang Hospital, Gumiro, Bundang-gu, Seongnam, Gyeonggi-do, Korea Correspondence to: Jeong Hun Kim, email: // Keywords : amyloid β, age-related macular degeneration, endocytosis, tight junction, receptor for advanced glycation end products,Gerotarget Received : September 10, 2015 Accepted : September 22, 2015 Published : September 29, 2015 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.