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Molecular and Cellular Biology, June 2006, p. 4327-4338, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.02393-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Phosphorylation of Amyloid Precursor Protein (APP) at Thr668 Regulates the Nuclear Translocation of the APP Intracellular Domain and Induces Neurodegeneration

Keun-A Chang,1 Hye-Sun Kim,1 Tae-Young Ha,1 Ji-Won Ha,1 Ki Young Shin,1 Yun Ha Jeong,1 Jean-Pyo Lee,3 Cheol-Hyoung Park,1 Seonghan Kim,1 Tae-Kyoung Baik,2 and Yoo-Hun Suh1*

Department of Pharmacology, College of Medicine, National Creative Research Initiative Center for Alzheimer's Dementia and Neuroscience Research Institute, MRC, Seoul National University, Seoul 110-799, South Korea,1 Department of Anatomy, College of Medicine, Eulji University, Daejeon 301-832, South Korea,2 Department of Pediatrics, School of Medicine, University of California at San Diego, La Jolla, California3

Received 15 December 2005/ Returned for modification 17 January 2006/ Accepted 8 March 2006

Amyloid precursor protein (APP) has eight potential phosphorylation sites in its cytoplasmic domain. Recently, it has demonstrated that the constitutive phosphorylation of APP at T668 (APP695 isoform numbering) was observed specifically in the brain. Neuron-specific phosphorylation of APP at T668 is thought to be important for neuronal functions of APP, although its exact physiological significance remains to be clarified. In this study, we show that the phosphorylation of the APP intracellular domain (AICD) at T668 is essential for its binding to Fe65 and its nuclear translocation and affects the resultant neurotoxicity, possibly mediated through the induction of glycogen synthase kinase 3ß and tau phosphorylation by enhancing the formation of a ternary complex with Fe65 and CP2 transcription factor. Taken together, these results suggest that the phosphorylation of AICD at T668 contributes to the neuronal degeneration in Alzheimer's disease (AD) by regulating its translocation into the nucleus and then affects neurodegeneration; therefore, the specific inhibitor of T668 phosphorylation might be the target of AD therapy.

* Corresponding author. Mailing address: Department of Pharmacology, College of Medicine, and National Creative Research Initiative Center for Alzheimer's Dementia, Seoul National University, Seoul 110-799, South Korea. Phone: 82 2 740 8285. Fax: 82 2 745 7996. E-mail: yhsuh{at}plaza.snu.ac.kr.

Molecular and Cellular Biology, June 2006, p. 4327-4338, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.02393-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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