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C-terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glycogen synthase kinase-3 beta expression

Title
C-terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glycogen synthase kinase-3 beta expression
Authors
Kim, HSKim, EMLee, JPPark, CHKim, SSeo, JHChang, KAYu, EJeong, SJChong, YHSuh, YH
Ewha Authors
정영해
SCOPUS Author ID
정영해scopus
Issue Date
2003
Journal Title
FASEB JOURNAL
ISSN
0892-6638JCR Link
Citation
vol. 17, no. 11, pp. 1951 - +
Keywords
Alzheimer's diseaseFe65CP2/LSF/LBP1 transcription factorAICD
Publisher
FEDERATION AMER SOC EXP BIOL
Indexed
SCI; SCIE; SCOPUS WOS
Abstract
The AICD ( amyloid precursor protein [APP] intracellular domain) and C31, the caspase-cleaved C-terminal fragment of APP, have been found in the brains of patients with Alzheimer's disease (AD). Here, we demonstrate for the first time that the C-terminal fragments of APP (AICD [C57, C59] and C31) exert neurotoxicity on differentiated PC 12 cells and rat primary cortical neurons by inducing the expression of glycogen synthase kinase 3beta, forming a ternary complex with Fe65 and CP2/LSF/LBP1 in the nucleus, whereas deletion mutants and a point mutant with Y682G of the YENPTY domain, a Fe65 binding domain, do not. Moreover, expression of APP770 and Swedish mutant form of APP increased the levels of C-terminal fragments of APP (APP-CTs) in neuronal cells and also induced the up-regulation of glycogen synthase kinase-3beta at both the mRNA and the protein levels. In addition, we show that CP2/LSF/LBP1 binding site (nt + 0 to similar to+ 10) in human glycogen synthase kinase 3beta promoter region is essential for the induction of the gene transcription by APP-CTs. The neurotoxicities induced by APP-CTs ( AICD and C31) were accompanied by an increase in the active form of glycogen synthase knase-3beta, and by the induction of tau phosphorylation and a reduction in nuclear beta-catenin levels, and led to apoptosis.
DOI
10.1096/fj.03-0106fje
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의학전문대학원 > 의학과 > Journal papers
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