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

Abstract

Intracellular amyloid beta (A beta) has been implicated in neuronal cell death in Alzheimer's disease (AD). Intracellular A beta also contributes to tight junction breakdown of retinal pigment epithelium (RPE) in age-related macular degeneration (AMD). Although A beta is predominantly secreted from neuronal cells, the mechanism of A beta transport into RPE remains to be fully elucidated. In this study, we demonstrated that intracellular A beta was found concomitantly with the breakdown of tight junction in RPE after subretinal injection of A beta into the mouse eye. We also presented evidence that receptor for advanced glycation end products (RAGE) contributed to endocytosis of A beta in RPE. siRNA-mediated knockdown of RAGE prevented intracellular A beta accumulation as well as subsequent tight junction breakdown in RPE. In addition, we found that RAGE-mediated p38 MAPK signaling contributed to endocytosis of A beta. Blockade of RAGE/p38 MAPK signaling inhibited A beta endocytosis, thereby preventing tight junction breakdown in RPE. These results implicate that intracellular A beta 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 A beta induced outer BRB breakdown in AMD.