Intracellular amyloid-β disrupts tight junctions of the retinal pigment epithelium via NF-κB activation

Abstract

Drusen are focal deposits between the retinal pigment epithelium (RPE) and Bruch's membrane in the retina of patients with age-related macular degeneration. Amyloid-beta is one of the important components of drusen, which leads to local inflammation. Furthermore, intracellular amyloid-beta disrupts tight junctions of the RPE. However, the intracellular mechanisms linking intracellular amyloid-beta and tightjunction disruption are not clear. In this study, intracellular amyloid-beta oligomers activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) p65, leading to the disorganization of tight junctions of the RPE in mice after subretinal injection of amyloid-beta. Amyloid-beta also triggered NF-kappa B activation in the RPE cells in confluent culture, which was inhibited by the suppression of the advanced glycosylation end product-specific receptor. NF-kappa B inhibition by an la kinase inhibitor prevented the suppression of expression of tight-junction proteins, zonula occuludens-1 and occludin in RPE cells. In addition, tight-junction complexes remained intact in the RPE of mice with NF-kappa B inhibition, although there were intracellular amyloid-beta oligomers. These data suggested that NF-kappa B inhibition might be a therapeutic approach to prevent amyloid-beta-mediated tight-junction disruption. (C) 2020 Elsevier Inc. All rights reserved.