RAGE-NF-κB-PPARγ Signaling is Involved in AGEs-Induced Upregulation of Amyloid-β Influx Transport in an In Vitro BBB Model

The receptor for advanced glycation end products (RAGE) at the blood-brain barrier (BBB) is critical for regulation of amyloid-beta (A beta) homeostasis in the diabetic brain. In this study, we used an in vitro BBB model consisting of mouse brain capillary endothelial cells (MBCECs) to investigate whether advanced glycation end products (AGEs) increase A beta influx transport across the BBB and the underlying mechanisms. We found that AGEs induced A beta influx transport across the BBB in concentration- and time-dependent manner, accompanied by increased RAGE expression and nuclear factor-kappa B p65 (NF-kappa B p65), and decreased nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma). Blockade of RAGE with its antibody and inhibition of NF-kappa B signaling with PDTC as well as activation of PPAR gamma with rosiglitazone significantly decreased A beta transport across the BBB from the periphery to the brain. These treatments also pronouncedly suppressed AGEs-induced increases in RAGE expression and nuclear NF-kappa B p65 and reversed the decrease in nuclear PPAR gamma. These results suggest that RAGE-NF-kappa B-PPAR gamma signaling is involved in regulation of AGEs-induced influx transport of A beta across the BBB and targeting the signaling pathway could serve as a novel strategy to modify such A beta transport.