APP signaling network

APP信令网

• 批准号: 8445194
• 负责人: Dale E. Bredesen
• 金额: $ 29.1万
• 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/8445194
• 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; Screening procedure; 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; 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. 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.

描述（由应用程序提供）：已在淀粉样蛋白肽（A peptice（A）上发表了超过50,000篇论文，该肽（a¿ （2）这种广泛生产的肽的物理功能尚不清楚。我们已经产生了具有许多斑块和高水平的A 42和42的转基因小鼠，但没有行为异常，电生理异常，突触损失或齿状循环萎缩（Galvan等，2006; Saganich等，2006; Saganich等，2006）。我们的结果表明，阿尔茨海默氏病是特定于物理信号传导的不平衡，在神经蛋白延伸涉及的信号和神经蛋白缩回涉及的信号之间，均由APP（淀粉样蛋白前体蛋白）介导。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并支持神经蛋白的扩展（Lourenco等，2009），而A ??与Netrin-1竞争APP并介导神经蛋白的缩回（Lu等，2003; Shaked等，2006）。这些结果还表明了A检验的身体作用，作为一种与Netrin-1竞争并介导物理神经缩回和细胞死亡的“抗营养蛋白”。我们已经开始剖析介导所得AD表型的下游网络。我们已经开发和利用了TAI（目标辅助迭代筛选），这是一种快速鉴定新型蛋白质 - 蛋白质相互作用者的方法（Kurakin和Bredesen，2002; Kurakin等，2003），以鉴定40种与应用程序相互作用的PDZ域相互作用的蛋白质，以识别应用程序相互作用的pdz romintor mint/X11家族蛋白。这些蛋白质提供了有关AD表型基础机制的新见解（Galvan等，2006； Swistowski等，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.这些结果还揭示了新的潜在治疗靶标。我们的长期目标是对介导阿尔茨海默氏病的细胞内信号传导途径进行全面的机械理解，从而揭示了新的治疗靶标。 公共卫生相关性：我们的长期目标是获得对介导阿尔茨海默氏病的细胞内信号传导途径的全面理解，揭示了新的治疗靶标。