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（由申请人提供）：已发表超过 50,000 篇关于淀粉样蛋白的论文-¿肽 (A¿) 聚集在阿尔茨海默病 (AD) 患者的大脑中，从而产生了许多具有两个共同点的理论：(1) A¿被认为通过化学和物理方式具有毒性，例如金属结合、活性氧产生和膜损伤；（2）这种广泛生产的肽的生理功能尚不清楚，我们已经培育出具有大量斑块和高水平的转基因小鼠。 A 水平40和42，但没有行为异常、电生理学异常、突触损失或齿状回萎缩（Galvan等人，2006；Saganich等人，2006）我们的结果表明阿尔茨海默氏病是生理信号失衡的另一种观点。 -具体来说，涉及神经突延伸和涉及神经突收缩的信号传导之间，两者均由 APP（淀粉样前体蛋白）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 并支持神经突延伸（Lourenco 等，2009），而 A¿与 netrin-1 竞争 APP 并介导神经突收缩（Lu et al., 2003；Shaked et al., 2006）。这些结果也表明 A¿ 的生理作用。 ，作为与 netrin-1 竞争并介导生理性神经突收缩和细胞死亡的“抗营养蛋白”，我们已经开始剖析介导 AD 表型的下游网络。 ），一种快速鉴定新型蛋白质-蛋白质相互作用因子的方法（Kurakin 和 Bredesen，2002 年；Kurakin 等人，2003 年），可鉴定 40 种相互作用的蛋白质与 APP 相互作用蛋白 Mint/X11 家族蛋白的 PDZ 结构域串联，这些蛋白为 AD 表型的潜在机制提供了新的见解（Galvan 等人，2006 年；Swistowski 等人，2009 年）。 ，就像三联复合体 AICD-Fe65-Tip60 可能参与转录一样（Cao 和 Sudhof， 2001；Baek et al.，2002），介导 APP 信号传导的转录复合物也可能包括 Mint/X11 蛋白及其相互作用的转录调节因子。我们的长期目标是获得对 APP 信号传导的全面机制了解。介导阿尔茨海默病的细胞内信号通路，揭示了新的治疗靶点。 公共健康相关性：我们的长期目标是对介导阿尔茨海默病的细胞内信号通路获得全面的机制理解，揭示新的治疗靶点。