APP signaling network

描述（由申请人提供）：关于阿尔茨海默病（AD）患者大脑中聚集的淀粉样蛋白-肽（A¿）的论文已经发表了5万多篇，导致许多理论有两个共同点：(1)通过化学和物理手段，例如金属结合，活性氧产生和膜损伤，A¿被认为是有毒的；(2)这种广泛产生的肽的生理功能尚不清楚。我们已经生产出具有大量斑块和高水平A¿40和42的转基因小鼠，但没有行为异常、电生理异常、突触丧失或齿状回萎缩（Galvan等人，2006；Saganich等人，2006）。我们的研究结果提出了另一种观点，即阿尔茨海默病是一种生理信号的不平衡，特别是涉及神经突延伸和涉及神经突收缩的信号之间的不平衡，两者都是由APP（淀粉样蛋白前体蛋白）介导的。我们已经确定了介导这两种拮抗作用的APP的替代配体：netrin-1结合APP并支持神经突延伸（Lourenco等人，2009），而A¿与netrin-1竞争APP并介导神经突收缩（Lu等人，2003；Shaked等人，2006）。这些结果还表明a¿的生理作用，作为一种“抗营养因子”，与netrin-1竞争，介导生理神经突收缩和细胞死亡。我们已经开始剖析介导AD表型的下游网络。我们开发并利用了TAIS（靶标辅助迭代筛选），这是一种鉴定新型蛋白-蛋白相互作用物的快速方法（Kurakin and Bredesen, 2002; Kurakin et al., 2003），鉴定了40种与APP相互作用物Mint/X11家族蛋白的PDZ结构域序列相互作用的蛋白。这些蛋白为阿尔茨海默病表型的潜在机制提供了新的见解（Galvan等，2006；Swistowski等，2009）。有趣的是，鉴定的40个蛋白中有14个是转录调节因子，这表明，正如三方复合体AICD-Fe65-Tip60可能参与转录（Cao and Sudhof, 2001; Baek et al., 2002），介导APP信号传导的转录复合体也可能包括Mint/X11蛋白及其相互作用的转录调节因子。这些结果也揭示了新的潜在治疗靶点。我们的长期目标是全面了解介导阿尔茨海默病的细胞内信号通路的机制，揭示新的治疗靶点。

DESCRIPTION (provided by applicant): Over 50,000 papers have been published on the amyloid-¿ peptide (A¿) that collects in the brains of patients with Alzheimer's disease (AD), leading to numerous theories that have two points in common: (1) A¿ is thought to be toxic by chemical and physical means, such as metal binding, reactive oxygen species production, and membrane damage; (2) the physiological function of this widely-produced peptide is unknown. We have produced transgenic mice with numerous plaques and high levels of A¿40 and 42, yet no behavioral abnormalities, electrophysiological abnormalities, synaptic loss, or dentate gyral atrophy (Galvan et al., 2006; Saganich et al., 2006). Our results suggest an alternative view of Alzheimer's disease as an imbalance in physiological signaling-specifically, between the signaling involved in neurite extension and that involved in neurite retraction, both mediated by APP (amyloid precursor protein). We have identified alternative ligands for APP that mediate these two antagonistic effects: netrin-1 binds APP and supports neurite extension (Lourenco et al., 2009), whereas A¿ competes with netrin-1 for APP and mediates neurite retraction (Lu et al., 2003; Shaked et al., 2006). These results also suggest a physiological role for A¿, as an "anti-trophin" that competes with netrin-1 and mediates physiological neurite retraction and cell death. We have begun to dissect the downstream network that mediates the resulting AD phenotype. We have developed and utilized TAIS (target-assisted iterative screening), a rapid approach to the identification of novel protein-protein interactors (Kurakin and Bredesen, 2002; Kurakin et al., 2003), to identify 40 proteins that interact with the PDZ domain tandem of the APP interactor Mint/X11 family proteins. These proteins provide new insights into the mechanisms underlying the AD phenotype (Galvan et al., 2006; Swistowski et al., 2009). Interestingly, 14 of the 40 proteins identified are transcriptional regulators, suggesting that, jut as the tripartite complex AICD-Fe65-Tip60 may be involved in transcription (Cao and Sudhof, 2001; Baek et al., 2002), transcriptional complexes mediating APP signaling may also include Mint/X11 proteins and their interacting transcriptional regulators. These results also reveal new potential therapeutic targets. Our long-term goal is to obtain a comprehensive mechanistic understanding of intracellular signaling pathways that mediate Alzheimer's disease, revealing new therapeutic targets. PUBLIC HEALTH RELEVANCE: Our long-term goal is to obtain a comprehensive mechanistic understanding of intracellular signaling pathways that mediate Alzheimer's disease, revealing new therapeutic targets.