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

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Abstract

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.

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Acknowledgements

We acknowledge the technical assistance of Dr. Feng Hao of XBL-China and Prof Yu Hui Xin of Jiangnan Institute of Nuclear Medicine. This work was supported by grants from the National Natural Science Foundation of China (81273497 to Hao Hong, 81603113 to Susu Tang), the Natural Science Foundation of Jiangsu Province (BK20150705 to Susu Tang), and the Program for Changjiang Scholars and Innovative Research Team in University (IRT1193), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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  1. Arijit Ghosh

    Present address: Department of Biomedical Sciences, City University of Hong Kong, HKSAR, China

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  1. Department of Pharmacology, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China

    Fang Chen, Arijit Ghosh, Mei Hu, Yan Long, Hongbin Sun, Lingyi Kong, Hao Hong & Susu Tang

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  1. Fang Chen
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Correspondence to Hao Hong or Susu Tang.

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Chen, F., Ghosh, A., Hu, M. et al. RAGE-NF-κB-PPARγ Signaling is Involved in AGEs-Induced Upregulation of Amyloid-β Influx Transport in an In Vitro BBB Model. Neurotox Res 33, 284–299 (2018). https://doi.org/10.1007/s12640-017-9784-z

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