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，大量的努力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。关键目标之一是了解APP在AD中的确切作用。APP明显参与AD的发病机制。例如，被鉴定为常染色体显性形式AD的原因的第一个基因突变在APP基因中。类似地，APP基因的重复是发展AD的风险因素。APP在神经元和神经胶质中均表达，虽然许多工作已经针对理解其在神经元中的作用或加工，但尚未检查APP在神经胶质中的表达和加工的重要性或相关性。因此，我们对APP在胶质细胞中的作用知之甚少。我们已经在果蝇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表达。当我们在神经胶质细胞中表达APP并与神经元表达相比时，我们发现APP沉积模式、APP加工和此类表达诱导的致死率均存在差异。我们进一步发现，致死率与除Abeta之外的特定加工肽严格相关;其水平随着人BACE的共表达而增加，并且与单独的APP表达相比导致更大的致死率。这些主要结果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APP在神经胶质细胞中表达的加工和致死效应，2）分析APP加工肽在脑中的神经胶质和神经元中表达的效应，和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，将大大有助于我们了解APP在胶质细胞中所起的作用及其对神经病理学和疾病发展的贡献。这些研究还可能识别APP介导的途径中的新参与者。