Deconstructing the pathogenic effect of APP in memory circuits

解构APP对记忆回路的致病作用

• 批准号: 8938903
• 负责人: JOANNA L JANKOWSKY
• 金额: $ 47.47万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8938903
• 关键词: Acute; Address; Adult; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Axon; Behavior; Behavioral; Biochemical; Biological Models; Biology; Brain; Cells; Dendrites; Development; Disease; Electrophysiology (science); Environment; Genetic study; Glutamates; Hippocampus (Brain); Impairment; In Vitro; Injection of therapeutic agent; Interneurons; Learning; Location; Maintenance; Measures; Memory; Modeling; Morphology; Mosaicism; Mus; Neonatal; Neuronal Dysfunction; Neurons; Pathogenesis; Pathway interactions; Pattern; Physiological; Physiology; Population; Positioning Attribute; Preparation; Production; Property; Proteins; Research Design; Role; Seminal; Side; Site; Slice; Source; Structure; Synapses; Synaptic Transmission; System; Testing; Tetanus Helper Peptide; Time; Transgenic Mice; Transgenic Organisms; Variant; Vertebral column; Viral; amyloid pathology; amyloid precursor protein processing; cell type; cognitive function; cognitive performance; density; excitatory neuron; flexibility; grasp; in vivo; inhibitory neuron; mouse model; mutant; neurogenesis; neuronal circuitry; neuronal excitability; overexpression; postnatal; postsynaptic; postsynaptic neurons; presynaptic; protein expression; public health relevance; research study; selective expression; synaptic function; synaptogenesis; transgene expression; transmission process

 DESCRIPTION (provided by applicant): Genetic studies have demonstrated a central role for the amyloid precursor protein (APP) in Alzheimer's disease, yet we do not understand at a cellular level how this protein contributes to disease. Endogenous APP is found in both excitatory and inhibitory neurons, but whether it exerts greater impact on one than the other has not yet been examined. We lack even a fundamental grasp of whether disease-associated APP variants primarily affect the neuron in which they are expressed, or instead act on neighboring cells within reach of secreted fragments. To address these fundamental questions about the basic biology and pathogenic potential of APP, we have developed a set of model systems that combine precise spatial control over the cells in which APP is expressed with reversible temporal control over when it is active. We will use these models to test our central hypothesis that the impact of pathogenic APP depends on both the timing and location of its expression. Our studies are designed to answer three main questions. In the first aim, we will examine whether pathogenic APP causes distinct impairments in circuit function and cognitive performance when expressed in excitatory vs. inhibitory neurons. We have already characterized the behavioral and hippocampal deficits evoked by excitatory APP expression, and here will create and characterize a mouse model in which APP is limited to GABAergic interneurons for comparison. In our second aim, we will examine how the position of APP-overexpressing cells within the hippocampus affects transmission through the trisynaptic circuit. We will use stereotaxic viral injection to selectively express pathogenic APP within presynaptic CA3 or postsynaptic CA1 neurons to determine which side of the synapse APP acts from and on to impair synaptic transmission in the Schaeffer collateral pathway. Finally, in our third aim, we will determine whether pathogenic APP affects neuronal function through a cell-autonomous or cell-extrinsic manner. We will use viral mosaicism to produce two complementary expression patterns in which isolated APP-overexpressing cells are surrounded by wild-type neurons, or in which isolated wild-type cells are surrounded by APP-overexpressing cells, to test how neuronal physiology is altered by APP expression within the neuron compared to APP expression within its neighbors. By using the tet-off transgenic system to restrict the location of APP in each of these models, we gain the added flexibility to control when it is expressed. This feature will allo us to distinguish the effects of pathogenic APP on synapse formation during postnatal development from its impact on synapse maintenance and plasticity in the adult. Moreover, by acutely arresting pathogenic APP expression in either of these settings, we will identify which physiological or behavioral changes are dependent on continued production of APP/Aß and which are permanent consequences of past exposure.

 描述（由适用提供）：遗传学研究表明，阿尔茨海默氏病在阿尔茨海默氏病中淀粉样蛋白前体蛋白（APP）的核心作用，但我们在细胞水平上不了解该蛋白如何对疾病贡献。内源性应用在兴奋性和抑制性神经元中都存在，但是尚未检查它是否对一个人施加比另一个影响更大的影响。我们缺乏对疾病相关的APP变体的基本掌握，主要是影响它们表达的神经元，还是对分泌片段触及的邻近细胞作用。为了解决有关APP基本生物学和致病潜力的这些基本问题，我们开发了一组模型系统，这些系统将精确的空间控制结合了对APP表达的细胞的精确空间控制，并在其活动中对其进行可逆的临时控制。我们将使用这些模型来检验我们的中心假设，即致病应用的影响取决于其表达的时间和位置。我们的研究旨在回答三个主要问题。在第一个目标中，我们将检查致病应用在兴奋性和抑制性神经元中表达时，病原应用程序是否会导致电路功能和认知性能的明显损害。我们已经表征了行为和海马来定义兴奋性应用程序表达式引起的诱发，此处将创建和表征一个鼠标模型，其中应用程序仅限于GABAERGIC INTERURONS进行比较。在我们的第二个目标中，我们将研究如何在海马中进行过表达的细胞的位置影响通过三触及电路的传播。我们将使用立体定位病毒注射在突触前CA3或突触后CA1神经元内有选择地表达致病性应用程序，以确定Synapse App的哪一侧从和上开始，以损害Schaeffer侧支途径中的突触传播。最后，在我们的第三个目标中，我们将通过细胞自主或细胞超支方式确定致病应用是否会影响神经元功能。我们将使用病毒镶嵌物产生两个完整的表达模式，其中孤立的APP过表达细胞被野生型神经元包围，或者与邻居中的App表达相比，神经元生理的App表达在APP表达中如何改变了APP Over Over表达细胞，其中孤立的野生型细胞被APP Over Over表达细胞所包围。通过使用Tet-Off转基因系统来限制这些模型中的应用程序的位置，我们会在表达时获得更多的灵活性来控制它。此功能将使我们区分致病性应用程序对产后发育过程中突触形成的影响与对成人突触维持和可塑性的影响。此外，通过在这两种环境中的任何一种情况下急性阻止致病APP表达，我们将确定哪些物理或行为变化取决于App/Aß的持续生产，哪些是过去暴露的永久后果。