C-terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glycogen synthase kinase-3beta expression.
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 approximately +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 kinase-3beta, and by the induction of tau phosphorylation and a reduction in nuclear beta-catenin levels, and led to apoptosis.
Kim
Hye-Sun
HS
Department of Pharmacology, College of Medicine, National Creative Research Initiative Center for Alzheimer's Dementia, Seoul National University, Seoul, 110-799, South Korea.
Kim
Eun-Mee
EM
Lee
Jean-Pyo
JP
Park
Cheol Hyoung
CH
Kim
Seonghan
S
Seo
Ji-Heui
JH
Chang
Keun-A
KA
Yu
Eunah
E
Jeong
Sung-Jin
SJ
Chong
Young Hae
YH
Suh
Yoo-Hun
YH
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D008957:Models, Genetic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D016716:PC12 Cells; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; C486242:Apbb1 protein, rat; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D016601:RNA-Binding Proteins; C501906:TFCP2 protein, human; D014157:Transcription Factors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3