Dissecting the Toxicity of Glial and Neuronal Expression of APP in the Brain

剖析大脑中 APP 的胶质细胞和神经元表达的毒性

• 批准号: 9205271
• 负责人: KRISHNA MOORTHI BHAT
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-15 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9205271
• 关键词: Adult; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Animal Model; Area; Axon; Biological; Biological Models; Biological Process; Biology; Brain; Cell membrane; Cells; Characteristics; Collection; Cytoplasm; Development; Disease; Drosophila genus; Enzymes; Evolution; Extracellular Space; Gene Mutation; Gene Proteins; Genes; Genetic; Genetic Screening; Goals; Grant; Human; Knowledge; Mediating; Membrane; Modeling; Neuroglia; Neurons; Orthologous Gene; Pathogenesis; Pathway interactions; Pattern; Peptides; Phenotype; Play; Presynaptic Terminals; Process; Protein Overexpression; Proteins; Research; Risk Factors; Role; Senile Plaques; System; Toxic effect; Vertebrates; Work; amyloid peptide; amyloid precursor protein processing; beta secretase; beta-site APP cleaving enzyme 1; cholinergic; conditional mutant; experimental study; fly; gain of function; neuropathology; novel; overexpression; protein expression; public health relevance; recessive genetic trait; screening; stem; tool

 DESCRIPTION (provided by applicant): Over the last several years, much effort has been devoted to studying the role of Amyloid Precursor Protein (APP) in Alzheimer's disease (AD). One of the key goals has been to understand the precise role of APP in AD. APP is clearly involved in the pathogenesis of AD. For instance, the first gene mutation identified as a cause for autosomal dominant form of AD is in the APP gene. Similarly, duplication for the APP gene is a risk factor for developing AD. APP is expressed both in neurons and glia, and while much work has been directed towards understanding its role or processing in neurons, the importance or the relevance of expression and the processing of APP in glia has not been examined. Thus, we know very little about the role of APP in glia in the development of AD. We have developed a robust APP-gain of function (APP-GOF) model in the Drosophila brain. We can express this specifically in glial cells or neurons. When we expressed APP in glia and compared to neuronal expression, we found differences in both the pattern of deposition of APP, processing of APP, and lethality induced by such expressions. We further found that the lethality strictly correlated with a specific processed peptide other than Abeta; the level of which increased with the co-expression of human BACE and resulted in a greater lethality compared to APP expression alone. These main results led us to formulate experiments to dissect the role of APP, its processing and toxicity when expressed in glial cells, and compare this with APP in neurons. Thus, our specific aims are: 1) Analyze the processing and the lethal effects of expression of APP in glial cells, 2) Analyze the effects of expression of processed peptides of APP in glia and neurons in the brain, and 3) Perform a conditional genetic screen for recessive modifiers of APP-GOF. We believe that these aims when completed, will contribute significantly to our understanding of the role played by APP in glia and its contribution to the development of the neuropathology and the disease. These studies will also likely identify new players in the APP-mediated pathway(s).

 描述（由申请人提供）：在过去的几年中，人们致力于研究淀粉样前体蛋白（APP）在阿尔茨海默病（AD）中的作用。主要目标之一是了解 APP 在 AD 中的确切作用。 APP显然参与了AD的发病机制。例如，第一个被确定为常染色体显性 AD 病因的基因突变位于 APP 基因中。同样，APP 基因的重复也是患 AD 的危险因素。 APP 在神经元和神经胶质细胞中表达，虽然许多工作都致力于了解其在神经元中的作用或处理，但 APP 在神经胶质细胞中表达和处理的重要性或相关性尚未得到检验。因此，我们对 APP 在神经胶质细胞中在 AD 发展中的作用知之甚少。我们在果蝇大脑中开发了一个强大的 APP 功能增益 (APP-GOF) 模型。我们可以在神经胶质细胞或神经元中特异性地表达这一点。当我们在神经胶质细胞中表达 APP 并与神经元表达进行比较时，我们发现 APP 的沉积模式、APP 的加工以及此类表达诱导的致死率存在差异。我们进一步发现，致死率与 Abeta 以外的特定加工肽严格相关；其水平随着人类 BACE 的共表达而增加，与单独表达 APP 相比，导致更大的致死率。这些主要结果促使我们制定实验来剖析 APP 的作用、其在神经胶质细胞中表达时的加工和毒性，并将其与神经元中的 APP 进行比较。因此，我们的具体目标是：1）分析神经胶质细胞中APP表达的加工和致死效应，2）分析神经胶质细胞和大脑神经元中APP加工肽表达的影响，以及3）对APP-GOF的隐性修饰物进行条件遗传筛选。我们相信，这些目标完成后，将极大地有助于我们了解 APP 在神经胶质细胞中所发挥的作用及其对神经病理学和疾病发展的贡献。这些研究也可能会确定 APP 介导途径中的新参与者。