The receptor for advanced glycation end products (RAGE) at the blood-brain barrier (BBB) is critical for regulation of amyloid-β (Aβ) 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 Aβ influx transport across the BBB and the underlying mechanisms. We found that AGEs induced Aβ influx transport across the BBB in concentration- and time-dependent manner, accompanied by increased RAGE expression and nuclear factor-kappa B p65 (NF-κB p65), and decreased nuclear peroxisome proliferator-activated receptor γ (PPARγ). Blockade of RAGE with its antibody and inhibition of NF-κB signaling with PDTC as well as activation of PPARγ with rosiglitazone significantly decreased Aβ transport across the BBB from the periphery to the brain. These treatments also pronouncedly suppressed AGEs-induced increases in RAGE expression and nuclear NF-κB p65 and reversed the decrease in nuclear PPARγ. These results suggest that RAGE-NF-κB-PPARγ signaling is involved in regulation of AGEs-induced influx transport of Aβ across the BBB and targeting the signaling pathway could serve as a novel strategy to modify such Aβ transport.
Keywords: Advanced glycation end products; Amyloid-β; Blood-brain barrier; NF-κB; Peroxisome proliferator-activated receptor γ; Receptor for advanced glycation end products.