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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）是淀粉样斑块的组分，淀粉样斑块是阿尔茨海默病（AD）的主要标志之一，并且与AD的病理学有关。Ap是由淀粉样蛋白P-蛋白前体（APP）的蛋白水解裂解产生的，APP是一种具有短胞内羧基末端的完整膜蛋白。APP的胞质尾区通过与胞质蛋白相互作用，调节APP的代谢和/或胞内转运。研究APP代谢的调控因子及其调控机制，对于寻找抑制APP生成的药物靶分子具有重要意义。我们已经分离出X11 L，一种神经元特异性的衔接蛋白，其结合APP的胞质结构域并抑制APP代谢，包括Ap的产生。我们发现一些细胞外刺激激活X11 L并促进与APP的结合。我们鉴定了X11 L氨基端一半的调节基序，X11 L可以被细胞外刺激激活，X11 L是一种潜在的抑制Ap生成的药物候选物。目前尚不清楚X11 L是否调节脑内APP代谢。为了解决这个问题，我们产生了缺乏X11 L表达的突变小鼠系（X11 L-KO小鼠）。在这种突变小鼠的大脑中，CTFp（APP的淀粉样蛋白生成片段）和Ap的生成与野生型小鼠大脑相比有所增加。我们的结果清楚地表明，X11 L在生理上调节脑内APP代谢。提示老年脑X11 L功能紊乱可能是散发型AD发病机制之一。