한빛사 논문
Abstract
Hye-Sun Kim, Eun-Mee Kim, Jean-Pyo Lee, Cheol Hyoung Park, Seonghan Kim, Ji-Heui Seo, Keun-A Chang, Eunah Yu, Sung-Jin Jeong, Young Hae Chong, and Yoo-Hun Suh
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 3β, 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-3β at both the mRNA and the protein levels. In addition, we show that CP2/LSF/LBP1 binding site (nt +0 to ~+10) in human glycogen synthase kinase 3β 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-3β, and by the induction of tau phosphorylation and a reduction in nuclear β-catenin levels, and led to apoptosis.
Key words: Alzheimer''s disease, Fe65, CP2/LSF/LBP1 transcription factor, AICD
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