APP, Alzheimer's Disease, and Synaptic Function

APP、阿尔茨海默病和突触功能

• 批准号: 7325715
• 负责人: Thomas C. Sudhof
• 金额: $ 52.51万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7325715
• 关键词: Abbreviations; Abeta synthesis; Accounting; Adaptor Signaling Protein; Address; Affect; Affinity Chromatography; Alzheimer' s Disease; Amino Acids; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Amyloidosis; Arctic Regions; Axonal Transport; Binding; Binding Proteins; Biochemical; Biochemical Genetics; Biochemistry; Biological; Biology; Blood Vessels; Brain; C-terminal; CRISP Thesaurus; Cell Surface Proteins; Cell Surface Receptors; Cells; Cellular biology; Cerebral Amyloid Angiopathy; Characteristics; Chromosome Pairing; Cleaved cell; Complex; Data; Development; Disease; Electron Microscopy; Endopeptidases; Etiology; Event; Extracellular Domain; Functional disorder; Gene Targeting; Genes; Genetic; Genetic Transcription; Genus Mentha; Goals; Golgi Apparatus; Human; Impaired cognition; In Vitro; Individual; Injury; Intracellular Membranes; Knock-out; Knockout Mice; Laboratories; Ligand Binding Domain; Ligands; Link; Localized; Mediating; Membrane Protein Traffic; Membrane Proteins; Modeling; Molecular; Molecular Biology; Molecular Chaperones; Morbidity - disease rate; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Nature; Nerve; Nerve Degeneration; Neurites; Neurons; Nuclear Export; Pathogenesis; Pathogenicity; Pathology; Patients; Peptide Hydrolases; Peptides; Phenotype; Physiological; Physiology; Positioning Attribute; Principal Investigator; Probability; Procedures; Production; Property; Protein Binding; Protein Precursors; Proteins; Proteolysis; Range; Rate; Reagent; Recombinants; Regulation; Reporting; Research Personnel; Role; Signal Transduction; Site; Synapses; Synaptic Vesicles; Testing; Thinking; Toxic effect; Transactivation; Transcriptional Activation; Transfection; Transmembrane Domain; Wild Type Mouse; abeta toxicity; base; cell growth regulation; density; experience; extracellular; follow-up; in vitro Model; insight; mortality; mouse model; mutant; neuronal survival; neurotoxicity; novel; novel strategies; programs; protein function; protein purification; receptor; research study; secretase; size; synaptic function; synaptogenesis; tool; trafficking; trans-Golgi Regions

DESCRIPTION (provided by applicant): Alzheimer's disease (AD), a major cause of morbidity and mortality, is caused at least in part by the toxicity of Abeta, a proteolytic product of a receptor-like protein called amyolid-beta precursor protein (APP). Although much progress was made in the understanding of how APP cleavage generates Abeta, the normal functions of APP, the relation of these functions to Abeta production and AD pathogenesis, and the mechanism by which Abeta damages neurons are incompletely understood. Recent studies suggest that AD is initially a disease of synapses, and that the characteristic cognitive impairment of early AD is due to a loss of synapse function. AD may affect synapses because synapses are exquisitely sensitive to injury, and/or because the function of APP acts directly or indirectly on synapses. The overall goal of the current application is to follow up on this hypothesis by utilizing the tools and reagents that our laboratory has developed to analyse synapse function. We aim to characterize the possible physiological role of APP at the synapse, and to examine how the synaptic etiology of AD is related to this physiological role. Since diverse functions have been associated with APP and a variety of mechanisms have been invoked in the pathogenesis of AD, this application proposes a wide spectrum of approaches ranging from cell biology and biochemical protein purification to genetic experiments in mice. These experiments will investigate the functions of APP, and relate these functions to the production and pathogenicity of Abeta. Specifically, we propose to identify and functionally characterize extracellular ligands for APP as a first approach to understanding the function of the conserved extracellular sequences of APP (specific aim 1), a goal that was already partially achieved in preliminary results with the isolation of specific APP ligands. We also propose to test the possible role of APP as a transcriptional regulator (specific aim 2), a role that we recently identified in transactivation experiments, and to analyze the functions of Mints, which bind to APP (specific aim 3). Furthermore, we propose to examine the relation of APP cleavage and Abeta production to intracellular membrane traffic and its regulation, and to test the physiological significance of APP cleavage (specific aim 4). Finally, we propose to clarify the question whether Abeta exerts a specifically synaptic toxicity, and to investigate the mechanism of its toxicity by using novel mouse models of AD that allow a more mechanistic approach than currently available models (specific aim 5). Together these studies will contribute to our understanding of APP function and Abeta toxicity in AD, and may suggest new avenues for interfering with the pathogenesis of AD.

描述（由申请人提供）：阿尔茨海默氏病（AD）是发病率和死亡率的主要原因，至少部分是由Abeta的毒性引起的，Abeta是一种被受体样蛋白的蛋白质水解产物，称为杏仁糖 - β前体蛋白（APP）。尽管在理解应用程序如何产生ABETA，APP的正常功能，这些功能与ABETA产生和AD发病机理的关系以及ABETA损害神经元的机制尚不完全了解的机制方面取得了很多进展。最近的研究表明，AD最初是一种突触疾病，并且早期AD的特征认知障碍是由于突触功能的丧失所致。 AD可能会影响突触，因为突触对损伤非常敏感，并且/或因为APP的功能直接或间接作用于突触。当前应用程序的总体目标是通过利用我们实验室开发的工具和试剂来分析突触功能，从而跟进这一假设。 我们旨在表征APP在突触中的生理作用，并研究AD的突触病因与该生理作用如何相关。由于多种功能已与APP相关联，并且在AD的发病机理中已经调用了多种机制，因此该应用提出了从细胞生物学和生化蛋白纯化到小鼠的遗传实验的广泛方法。这些实验将研究APP的功能，并将这些功能与Abeta的生产和致病性联系起来。具体而言，我们建议识别和在功能上表征APP的细胞外配体作为理解APP的保守细胞外序列功能的第一种方法（特定AIM 1），这一目标是通过隔离特定APP配体的初步结果中部分实现的目标。我们还建议测试APP作为转录调节剂的可能作用（特定目标2），这是我们最近在反式激活实验中确定的作用，并分析与APP结合的薄荷功能（特定目标3）。此外，我们建议研究应用程序裂解和ABETA生产与细胞内膜流量及其调节的关系，并测试应用程序裂解的生理意义（特定目标4）。最后，我们建议澄清一个问题Abeta是否具有特异性突触毒性，并通过使用新型的AD模型来研究其毒性的机制，该AD的新型AD模型比当前可用的模型更具机械性方法（特定的AIM 5）。这些研究将共同​​有助于我们对AD中的应用功能和ABETA毒性的理解，并可能提出了干扰AD发病机理的新途径。

项目成果

Deletion of Mint proteins decreases amyloid production in transgenic mouse models of Alzheimer's disease.

• DOI: 10.1523/jneurosci.2481-08.2008
• 发表时间: 2008-12-31
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Ho A;Liu X;Südhof TC
• 通讯作者: Südhof TC