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Phosphorylation of amyloid precursor protein (APP) at Thr668 regulates the nuclear translocation of the APP intracellular domain and induces neurodegeneration

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Authors
Chang, Keun-A; Kim, Hye-Sun; Ha, Tae-Young; Ha, Ji-Won; Shin, Ki Young; Jeong, Yun Ha; Lee, Jean-Pyo; Park, Cheol-Hyoung; Kim, Seonghan; Baik, Tae-Kyoung; Suh, Yoo-Hun
Issue Date
2006-05-18
Publisher
American Society for Microbiology
Citation
Mol. Cell. Biol. 26:4327-4338
Abstract
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 3beta 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.
ISSN
0270-7306
Language
English
URI
http://hdl.handle.net/10371/9696
DOI
https://doi.org/10.1128/MCB.02393-05
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College of Medicine/School of Medicine (의과대학/대학원)Pharmacology (약리학전공)Journal Papers (저널논문_약리학전공)
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