Cho H J, Son S M, Jin S M, Hong H S, Shin D H, Kim S J, Huh K, Mook-Jung I
Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, 28 Yungun-dong, Jongro-gu, Seoul, 110-799, Korea.
FASEB J. 2009 Aug;23(8):2639-49. doi: 10.1096/fj.08-126383. Epub 2009 Mar 30.
The receptor for advanced glycation end products (RAGE) is a multiligand cell surface receptor, and amyloid beta peptide (Abeta) is one of the ligands for RAGE. Because RAGE is a transporter of Abeta 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 Abeta production was examined in the brain tissue of an AD animal model, Tg2576 mice, as well as cultured cells. Because beta-site APP-cleaving enzyme 1 (BACE1), an essential protease for Abeta production, is up-regulated in cells overexpressing RAGE and in RAGE-injected brains of Tg2576 mice, the molecular mechanisms underlying RAGE, BACE1 expression, and Abeta 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 Abeta 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, Abeta, 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 Abeta production and deposition in the brain.
晚期糖基化终末产物受体（RAGE）是一种多配体细胞表面受体，淀粉样β肽（Aβ）是RAGE的配体之一。由于RAGE是Aβ从血液转运至大脑的载体，因此人们认为RAGE在阿尔茨海默病（AD）发病机制中起重要作用。在本研究中，我们在AD动物模型Tg2576小鼠的脑组织以及培养细胞中研究了RAGE在Aβ产生中的作用。由于β-位点淀粉样前体蛋白裂解酶1（BACE1）是Aβ产生所必需的蛋白酶，在过表达RAGE的细胞以及注射RAGE的Tg2576小鼠大脑中上调，因此我们研究了RAGE、BACE1表达及Aβ产生的分子机制。由于RAGE刺激细胞内钙，因此我们检测了活化T细胞核因子1（NFAT1）。RAGE诱导BACE1表达继而产生Aβ后，NFAT1被激活。与注射全长RAGE（fRAGE）的Tg2576小鼠相比，向老年Tg2576小鼠脑内注射作为fRAGE竞争剂的可溶性RAGE（sRAGE）可降低斑块、Aβ、BACE1及NFAT1活性形式的水平。综上所述，RAGE通过激活NFAT1刺激功能性BACE1表达，导致大脑中产生更多Aβ并沉积。
