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

Cited 83 time in Web of Science Cited 91 time in Scopus
Authors
Cho, H J; Son, S M; Jin, S M; Hong, H S; Shin, D H; Kim, S J; Huh, K; Mook-Jung, I
Issue Date
2009-04-01
Publisher
Federation of American Society of Experimental Biology
Citation
Faseb Journal 23(8), 2639-2649
Keywords
Alzheimer Disease/etiology/*metabolism/pathologyAmyloid Precursor Protein Secretases/*biosynthesisAmyloid beta-Protein/*biosynthesis/metabolism/pharmacologyAnimalsAspartic Endopeptidases/*biosynthesisBase SequenceBinding Sites/geneticsBrain/metabolismCell LineDisease Models, AnimalHumansMiceMice, TransgenicNFATC Transcription Factors/*metabolismOligonucleotide Probes/geneticsPeptide Fragments/metabolism/pharmacologyReceptors, Immunologic/chemistry/genetics/*metabolismRecombinant Proteins/chemistry/genetics/metabolismSenile Plaques/metabolism/pathologySolubility
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.
ISSN
1530-6860 (Electronic)
Language
English
URI
http://www.fasebj.org/cgi/reprint/23/8/2639.pdf

http://hdl.handle.net/10371/67468
DOI
https://doi.org/10.1096/fj.08-126383
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Biochemistry & Molecular Biology (생화학교실)Journal Papers (저널논문_생화학교실)
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