APP signaling network

APP信令网

• 批准号: 8550744
• 负责人: Dale E. Bredesen
• 金额: $ 22.92万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8550744
• 关键词: Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Atrophic; Behavioral; Binding; Biological Assay; Brain; Cell Death; Cell Line; Co-Immunoprecipitations; Complex; Confocal Microscopy; Deposition; Disease Progression; Event; Gene Activation; Genetic Transcription; Genus Mentha; Goals; Immunohistochemistry; In Vitro; Laboratories; Link; Luciferases; Mediating; Mediator of activation protein; Membrane; Metals; Methods; Mus; Neurites; Nuclear; Organ Size; Paper; Pathogenesis; Pathway interactions; Patients; Peptides; Phenotype; Physiological; Poison; Process; Production; Protein Family; Protein Overexpression; Proteins; Publishing; Reactive Oxygen Species; Role; Signal Pathway; Signal Transduction; Staging; Synapses; System; Therapeutic; Toxic effect; Transactivation; Transcriptional Coactivator with PDZ-Binding Motif; Transgenic Mice; Western Blotting; X11 protein; amyloid precursor protein ligand; base; cerebral atrophy; design; disease phenotype; human NTN1 protein; in vivo; insight; mouse model; mutant; netrin-1; neuron loss; new therapeutic target; novel; prevent; protein complex; protein protein interaction; screening; theories; therapeutic target

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.

描述（申请人提供）：关于聚集在阿尔茨海默病（AD）患者大脑中的淀粉样肽（A），已发表了超过50，000篇论文，导致许多理论，这些理论有两个共同点：（1）A被认为是有毒的化学和物理手段，如金属结合，活性氧物质的产生和膜损伤;（2）这种广泛生产的肽的生理功能是未知的。我们已经产生了具有许多斑块和高水平A 40和42的转基因小鼠，但没有行为异常、电生理异常、突触丢失或齿状回萎缩（Galvan等人，2006; Saganich等人，2006年）。我们的研究结果表明，阿尔茨海默病的另一种观点是生理信号的不平衡，特别是神经突延伸和神经突收缩所涉及的信号之间的不平衡，两者都由APP（淀粉样前体蛋白）介导。我们已经鉴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 et al.，2003; Shaked等人，2006年）。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竞争并介导生理性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。我们已经开发并利用了TAIS（目标辅助迭代筛选），这是一种鉴定新型蛋白质-蛋白质相互作用物的快速方法（Kurakin和Bredesen，2002; Kurakin等人，2003），以鉴定与APP相互作用物Mint/X11家族蛋白的PDZ结构域串联体相互作用的40种蛋白。这些蛋白质为AD表型的潜在机制提供了新的见解（Galvan等人，2006; Swistowski等人，2009年）。有趣的是，所鉴定的40种蛋白质中有14种是转录调节因子，这表明除了三重复合物AICD-Fe 65-Tip 60之外，还可能参与转录（Cao和Sudhof，2001; Baek等人，2002），介导APP信号传导的转录复合物还可以包括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。我们的长期目标是获得介导阿尔茨海默病的细胞内信号通路的全面机制理解，揭示新的治疗靶点。