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RAGE regulates BACE1 and Abeta generation via NFAT1 activation in Alzheimer's disease animal model.

Authors
Cho, HJ; Son, SM; Jin, SM; Hong, HS; Shin, DH; Kim, SJ; Huh, K; Mook-Jung, I
Citation
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 23(8):2639-2649, 2009
Journal Title
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN
0892-66381530-6860
Abstract
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.
MeSH terms
Alzheimer Disease/etiologyAlzheimer Disease/metabolism*Alzheimer Disease/pathologyAmyloid Precursor Protein Secretases/biosynthesis*Amyloid beta-Protein/biosynthesis*Amyloid beta-Protein/metabolismAmyloid beta-Protein/pharmacologyAnimalsAspartic Acid Endopeptidases/biosynthesis*Base SequenceBinding Sites/geneticsBrain/metabolismCell LineDisease Models, AnimalHumansMiceMice, TransgenicNFATC Transcription Factors/metabolism*Oligonucleotide Probes/geneticsPeptide Fragments/metabolismPeptide Fragments/pharmacologyReceptors, Immunologic/chemistryReceptors, Immunologic/geneticsReceptors, Immunologic/metabolism*Recombinant Proteins/chemistryRecombinant Proteins/geneticsRecombinant Proteins/metabolismSenile Plaques/metabolismSenile Plaques/pathologySolubility
DOI
10.1096/fj.08-126383
PMID
19332646
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Neurology
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