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RAGE regulates BACE1 and Aβ generation via NFAT1 activation in Alzheimer’s disease animal model

H. J. Cho^*, S. M. Son^*, S. M. Jin^*, H. S. Hong^*, D. H. Shin^,, S. J. Kim^,, K. Huh and I. Mook-Jung^*,1

^* Department of Biochemistry and Biomedical Sciences,

Department of Physiology, and

Ischemia/Hypoxia Disease Institute, Seoul National University College of Medicine, Seoul, Korea; and

Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Korea

¹ Correspondence: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, 28 Yungun-dong, Jongro-gu, Seoul, 110-799, Korea. E-mail: inhee{at}snu.ac.kr

The receptor for advanced glycation end products (RAGE) is a multiligand cell surface receptor, and amyloid β peptide (Aβ) is one of the ligands for RAGE. Because RAGE is a transporter of Aβ from the blood to the brain, RAGE is believed to play an important role in Alzheimer’s disease (AD) pathogenesis. In the present study, the role of RAGE in Aβ production was examined in the brain tissue of an AD animal model, Tg2576 mice, as well as cultured cells. Because β-site APP-cleaving enzyme 1 (BACE1), an essential protease for Aβ production, is up-regulated in cells overexpressing RAGE and in RAGE-injected brains of Tg2576 mice, the molecular mechanisms underlying RAGE, BACE1 expression, and Aβ production were examined. Because RAGE stimulates intracellular calcium, nuclear factor of activated T-cells 1 (NFAT1) was examined. NFAT1 was activated following RAGE-induced BACE1 expression followed by Aβ generation. Injection of soluble RAGE (sRAGE), which acts as a competitor with full-length RAGE (fRAGE), into aged Tg2576 mouse brains reduced the levels of plaques, Aβ, BACE1, and the active form of NFAT1 compared with fRAGE-injected Tg2576 mice. Taken together, RAGE stimulates functional BACE1 expression through NFAT1 activation, resulting in more Aβ production and deposition in the brain.—Cho, H. J., Son, S. M., Jin, S. M., Hong, H. S., Shin, D. H., Kim, S. J., Huh, K., Mook-Jung, I. RAGE regulates BACE1 and Aβ generation via NFAT1 activation in Alzheimer’s disease animal model.

Key Words: Tg2576 • plaques • intracellular calcium • secretase • AGE • SH-SY5Y