June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
The effect of intracellular Aβ uptake via RAGE on tight junction in retinal pigment epithelium
Author Affiliations & Notes
  • Sung Wook Park
    FARB, Department of Ophthalmology, Seoul National University Hospital, Seoul
    Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
  • Jin Hyoung Kim
    FARB, Department of Ophthalmology, Seoul National University Hospital, Seoul
  • Sang Min Park
    Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea (the Republic of)
  • Minho Moon
    Molecular Neurobiology Laboratory, McLean Hospital/Harvard Medical School, Belmont, MA
  • Kihwang Lee
    Ophthalmology, Ajou University School of Medicine, Suwon, Korea (the Republic of)
  • Kyu Hyung Park
    Ophthalmology, Seoul National University Bundang Hospital, Seongnam, Korea (the Republic of)
  • Woo Jin Park
    Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea (the Republic of)
  • Jeong Hun Kim
    FARB, Department of Ophthalmology, Seoul National University Hospital, Seoul
    Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea (the Republic of)
  • Footnotes
    Commercial Relationships Sung Wook Park, None; Jin Hyoung Kim, None; Sang Min Park, None; Minho Moon, None; Kihwang Lee, None; Kyu Hyung Park, None; Woo Jin Park, None; Jeong Hun Kim, None
  • Footnotes
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Investigative Ophthalmology & Visual Science June 2015, Vol.56, 2326. doi:
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      Sung Wook Park, Jin Hyoung Kim, Sang Min Park, Minho Moon, Kihwang Lee, Kyu Hyung Park, Woo Jin Park, Jeong Hun Kim; The effect of intracellular Aβ uptake via RAGE on tight junction in retinal pigment epithelium. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2326.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Intracellular amyloid beta (Aβ) has been implicated in neuronal cell death in Alzheimer’s disease (AD) and tight junction breakdown of retinal pigment epithelium (RPE) in age-related macular degeneration (AMD). Although Aβ is predominantly secreted from the neuronal cells, the mechanism of Aβ transport into the RPE remain to be fully elucidated. This study is aimed to demonstrate the role of receptor for advanced glycation end products (RAGE) in intracellular Aβ transport and the role of intracellular Aβ in RPE tight junction.

Methods: To evaluate cellular uptake of Aβ in RPE, subretinal injection of Aβ42 or PBS (control) was performed in C57BL/6J mice (N=6). Seven days after subretinal Aβ42 injection, RPE/choroid/scleral complex was flat-mounted. Then, Aβ and ZO-1 were immunostained and observed under confocal microscope. To determine the mechanism how extracellular Aβ translocate into intracellular space in RPE, we immunostained plasma membrane using biotinylation or RAGE after exogenous OAβ42 treatment. Western blot analysis for Aβ and p38 MAPK was performed to investigate the role of RAGE on Aβ uptake in RPE cells using RAGE siRNA or p38 inhibitor (SB 203580). To determine the role of RAGE on barrier function of RPE after Aβ treatment, we measured transepithelial resistance in RPE.

Results: Intracellular Aβ was found concomitantly with breakdown of tight junction in the RPE after subretinal injection of Aβ into the mouse eye. We also presented evidence that RAGE contributed to endocytosis of Aβ in the RPE. siRNA mediated RAGE knockdown prevented RAGE mediated endocytosis of Aβ and subsequent tight junction breakdown in RPE. RAGE-mediated P38 MAPK signaling contributed to endocytosis of Aβ. Blockade of RAGE inhibited Aβ endocytosis, thereby preventing tight junction breakdown in RPE.

Conclusions: Intracellular Aβ via the RAGE/p38 MAPK-mediated endocytosis contributes to breakdown of tight junction in RPE. Thus, we suggest that RAGE could be a potential therapeutic target for intracellular Aβ induced outer BRB breakdown in AMD.

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