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

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 ag...