The breakdown of tight junction in retinal pigment epithelium by Aβ via RAGE signaling pathway

Abstract

Purpose : Amyloid beta (Aβ) has been implicated in the pathogenesis of age-related macular degeneration (AMD). Although Aβ is predominantly secreted from the neuronal cells, the mechanism how extracellular Aβ decrease tight junction in RPE remain to be fully elucidated. This study is aimed to demonstrate the role of receptor for advanced glycation end products (RAGE) signaling pathway in Aβ induced breakdown of tight junction in RPE.

Methods : To evaluate in vivo effect of exogenous Aβ on tight junction in RPE, subretinal injection of Aβ₄₂ or PBS was performed in C57BL/6J mice. Then, Aβ and ZO-1 were evaluated in RPE/choroid/scleral complex. Using immunocytochemistry and western blot, we determined the signaling pathway after Aβ₄₂ treatment in ARPE-19 cells. We also evaluate the effect of RAGE siRNA and NF-Kb inhibitor in Aβ induced tight junction breakdown. To determine the role of RAGE signaling in vivo, we evaluated tight junction after Aβ treatment with NF-Kb inhibitor.

Results : Aβ induced breakdown of tight junction in the RPE after subretinal injection of Aβ into the mouse eye. We also presented evidence that various downstream signaling of RAGE was activated by Aβ in the RPE. siRNA mediated RAGE knockdown or NF-KB inhibitor prevented tight junction breakdown in RPE. Blockade of NF-Kb protected Aβ induced breakdown of tight junction in RPE.

Conclusions : Our data demonstrates that Aβ activated RAGE signaling pathway and induced breakdown of tight junction in RPE. Thus, we suggest that RAGE could be a potential therapeutic target for Aβ induced outer BRB breakdown in AMD.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.