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
Department of Pharmacology, College of Medicine, and National Creative Research Initiative Center for Alzheimer's Dementia, Seoul National University, Seoul 110-799, South Korea.
Mol Cell Biol. 2006 Jun;26(11):4327-38. doi: 10.1128/MCB.02393-05.
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.
淀粉样前体蛋白（APP）在其胞质结构域中有八个潜在的磷酸化位点。最近，已证明在大脑中特异性观察到APP在T668（APP695亚型编号）处的组成型磷酸化。尽管其确切的生理意义仍有待阐明，但APP在T668处的神经元特异性磷酸化被认为对APP的神经元功能很重要。在本研究中，我们表明APP细胞内结构域（AICD）在T668处的磷酸化对于其与Fe65的结合及其核转位至关重要，并影响由此产生的神经毒性，这可能是通过增强与Fe65和CP2转录因子形成三元复合物来诱导糖原合酶激酶3β和tau磷酸化介导的。综上所述，这些结果表明AICD在T668处的磷酸化通过调节其向细胞核的转位，进而影响神经退行性变，从而导致阿尔茨海默病（AD）中的神经元变性；因此，T668磷酸化的特异性抑制剂可能是AD治疗的靶点。
