Analysis of intracellular of APP metabolism and exploration of novel targets of drug suppressing Aβ generation

细胞内APP代谢分析及药物抑制Aβ生成新靶点探索

基本信息

批准号：
16209002
负责人：
SUZUKI Toshiharu
金额：
$ 31.03万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16209002/
关键词：
Alzheimer's disease p-amyloid APP neurodegenerative disease gene knockout mouse drug development 神経変性 X11L 代謝 Alcadein ADAM セクリターゼ神経 β-アミロイド神経変性疾患

项目摘要

The amyloid p-protein (Ap) is a component of amyloid plaques, one of the major hallmarks of Alzheimer's disease (AD), and is implicated in the pathology of AD. Ap is generated by proteolytic cleavage of the amyloid p-protein precursor (APP), an integral membrane protein with a short intracellular carboxyl terminus. The cytoplasmic tail of APP corresponds to the regulation of metabolism and/or intracellular transport of APP by interacting with cytoplasmic proteins. To revel the regulators in APP metabolism and to understand the regulatory mechanism are important to find novel target molecules for drug development suppressing Ap generation. We have isolated X11L, a neuron-specific adaptor protein, which binds to the cytoplasmic domain of APP and suppresses APP metabolism including Ap generation. We found that some extracellular stimulus activates XIlL and facilitates the association with APP. We identified regulatory motif on the amino-terminal half of X11L, while the middle PI domain bound to the APP. Our current observations showed that X11L can be activated by extracellular stimulus and that X11L is a potential candidate for drug development in the suppression of Ap generation.In contrast to these in vitro study with cells, it is sill unclear whether the X11L regulates APP metabolism in brain. To resolve this issue, we generated mutant mouse line lacking X11L expression (X11L-KO mouse). In the brain of this mutant mouse, the generation of CTFp, a amyloidogenic fragment of APP, and Ap increased when compared with it in the wild-type mouse brain. Our result clearly showed that X11L regulates APP metabolism physiologically in brain. Present results suggest that functional disorder of X11L in the aged brain may cause the pathogenesis of sporadic type of AD.

淀粉样蛋白P蛋白（AP）是淀粉样斑的组成部分，淀粉样蛋白是阿尔茨海默氏病（AD）的主要特征之一，与AD的病理有关。 AP是由淀粉样蛋白P蛋白前体（APP）的蛋白水解切割产生的，淀粉样蛋白Protein Prombrane蛋白具有短的细胞内羧基末端。 APP的细胞质尾巴通过与细胞质蛋白相互作用，对应于代谢和/或APP的细胞内转运。为了启用APP代谢中的调节剂并了解调节机制对于找到用于抑制AP产生的药物开发的新目标分子很重要。我们具有分离的X11L，一种神经元特异性衔接蛋白，它与APP的细胞质结构域结合，并抑制了包括AP生成在内的APP代谢。我们发现一些细胞外刺激会激活Xill并促进与应用程序的关联。我们在X11L的氨基末端一半上确定了调节基序，而中间PI结构域与应用程序结合。我们目前的观察结果表明，X11L可以通过细胞外刺激激活，X11L是抑制AP生成的药物开发的潜在候选者。与这些细胞的体外研究相反，X11L是否调节App App代谢中的代谢是否在脑。为了解决此问题，我们生成了缺乏X11L表达（X11L-KO小鼠）的突变鼠标线。在这种突变小鼠的大脑中，与野生型小鼠脑相比，CTFP的产生，APP的淀粉样蛋白生成片段和AP增加。我们的结果清楚地表明，X11L在大脑中在生理上调节APP代谢。目前的结果表明，老年大脑中X11L的功能障碍可能导致AD零星类型的发病机理。