Taru Hidenori, Yoshikawa Kazuaki, Suzuki Toshiharu
Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi -6, Kita-ku, Sapporo 060-0812, Japan.
FEBS Lett. 2004 Jun 4;567(2-3):248-52. doi: 10.1016/j.febslet.2004.04.077.
beta-Amyloid precursor protein (APP) is a type I transmembrane protein. Its cleavages by beta- and gamma-secretases yield beta-amyloid, which is the main constituent of senile plaques in Alzheimer's disease (AD). In apoptotic cells and AD brains, APP is alternatively cleaved by caspases in the cytoplasmic region after the Asp664 residue (with respect to the numbering conversion for the APP695 isoform). Caspase-cleaved fragments of APP are cytotoxic and have been implicated in AD pathogenesis; however, the mechanisms regulating the cleavage have not been studied. APP is constitutively phosphorylated at Thr668 in brain. In the present study, we demonstrate that APP phosphorylated at Thr668 is less vulnerable to cytoplasmic cleavage by caspase-3 and caspase-8. This suggests that APP phosphorylation suppresses the generation of caspase-cleaved fragments of APP in the brain and that perturbation of this phosphorylation may be involved in APP-mediated neurotoxicity.
β-淀粉样前体蛋白（APP）是一种I型跨膜蛋白。它被β-分泌酶和γ-分泌酶切割后产生β-淀粉样蛋白，这是阿尔茨海默病（AD）中淀粉样斑块的主要成分。在凋亡细胞和AD大脑中，APP在Asp664残基（相对于APP695异构体的编号转换）之后在细胞质区域被半胱天冬酶选择性切割。APP的半胱天冬酶切割片段具有细胞毒性，并与AD发病机制有关；然而，调节这种切割的机制尚未得到研究。APP在大脑中Thr668位点持续磷酸化。在本研究中，我们证明在Thr668位点磷酸化的APP对caspase-3和caspase-8的细胞质切割更具抗性。这表明APP磷酸化抑制了大脑中APP半胱天冬酶切割片段的产生，并且这种磷酸化的扰动可能与APP介导的神经毒性有关。
