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C‐terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glycogen synthase kinase‐3β expression
Author(s) -
Kim Hye-Sun,
Kim Eun-Mee,
Lee Jean-Pyo,
Park Cheol Hyoung,
Kim Seonghan,
Seo Ji-Heui,
Chang Keun-A,
Yu Eunah,
Jeong Sung-Jin,
Chong Young Hae,
Suh Yoo-Hun
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0106fje
Subject(s) - gsk 3 , glycogen synthase , amyloid precursor protein , gsk3b , microbiology and biotechnology , phosphorylation , chemistry , kinase , neurotoxicity , intracellular , biology , biochemistry , alzheimer's disease , medicine , disease , organic chemistry , toxicity
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.