Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3|[beta]| expression

doi:doi:10.1038/sj.cdd.4401928

Cell Death and Differentiation (2007) 14, 79–91. doi:10.1038/sj.cdd.4401928; published online 28 April 2006

Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3 expression

Edited by P Nicotera

Y Xu^1,2,5, H-S Kim^1,5, Y Joo¹, Y Choi¹, K-A Chang¹, C H Park¹, K-Y Shin¹, S Kim¹, Y-H Cheon³, T-K Baik³, J-H Kim⁴ and Y-H Suh¹

¹Department of Pharmacology, College of Medicine, National Creative Research Initiative Center for Alzheimer's Dementia and Neuroscience Research Institute, MRC, Seoul National University, Seoul, South Korea
²Department of Preventive Medicine, Yanbian University College of Medicine, Yanj City, Jilin Province, China
³Department of Anatomy, College of Medicine, Eulji University, Daejeon, South Korea
⁴Department of Life Sciences and Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk, Korea
⁵These authors contributed equally to this work

Correspondence: Professor Y-H Suh, Department of Pharmacology, College of Medicine, National Creative Research Initiative Center for Alzheimer's Dementia, Seoul National University, Seoul, 110-799, South Korea. Tel: +82-2-740-8285; Fax: +82-2-745-7996; E-mail: yhsuh@plaza.snu.ac.kr

Received 4 August 2005; Revised 26 January 2006; Accepted 1 March 2006; Published online 28 April 2006.

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Abstract

Amyloid precursor protein (APP) is a member of a gene family that includes two APP-like proteins, APLP1 and 2. Recently, it has been reported that APLP1 and 2 undergo presenilin-dependent -secretase cleavage, as does APP, resulting in the release of an $approx$ 6 kDa intracellular C-terminal domain (ICD), which can translocate into the nucleus. In this study, we demonstrate that the APLP2-ICDs interact with CP2/LSF/LBP1 (CP2) transcription factor in the nucleus and induce the expression of glycogen synthase kinase 3 (GSK-3), which has broad-ranged substrates such as - and -catenin. The significance of this finding is substantiated by the in vivo evidence of the increase in the immunoreactivities for the nuclear C-terminal fragments of APLP2, and for GSK-3 in the AD patients' brain. Taken together, these results suggest that APLP2-ICDs contribute to the AD pathogenesis, by inducing GSK-3 expression through the interaction with CP2 transcription factor in the nucleus.

Keywords:

amyloid precursor-like protein 2, Alzheimer's disease, CP2 transcription factor, Fe65, GSK-3,

Abbreviations:

APLP, amyloid precursor like protein; APP, amyloid precursor protein; AICD, APP intracellular domain; A, amyloid beta protein; AD, Alzheimer's disease; PTB, phosphotyrosine binding domain; GSK-3, glycogen synthase kinase-3; CTFs, C-terminal fragments; C57, C50, 57, 50 amino-acid residues carboxy terminal fragment of APLP2; C57^Y738G, C50^Y738G, Y738G point mutated C57, C50; HEK, human embryonic kidney; DAPT, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine -butyl ester; NGF, nerve growth factor; NFT, neurofibrillary tangle