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C-terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glycogen synthase kinase-3 beta expression
- C-terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glycogen synthase kinase-3 beta expression
- Kim, HS; Kim, EM; Lee, JP; Park, CH; Kim, S; Seo, JH; Chang, KA; Yu, E; Jeong, SJ; Chong, YH; Suh, YH
- Ewha Authors
- SCOPUS Author ID
- Issue Date
- Journal Title
- FASEB JOURNAL
- vol. 17, no. 11, pp. 1951 - +
- Alzheimer's disease; Fe65; CP2/LSF/LBP1 transcription factor; AICD
- FEDERATION AMER SOC EXP BIOL
- SCI; SCIE; SCOPUS
- 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.
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