A Novel Drosophila Model to Understand the Role of Innate Immunity in Alzheimer's Disease

一种新的果蝇模型来了解先天免疫在阿尔茨海默病中的作用

• 批准号: 9891933
• 负责人: Nathan Terry Mortimer
• 金额: $ 14.7万
• 依托单位: ILLINOIS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891933
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease therapy; American; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Autoimmune Responses; Autoimmunity; Biological; Biological Assay; Biological Models; Cell model; Cells; Cellular Immunity; Complex; Dementia; Development; Disease; Drosophila genus; Drosophila melanogaster; Ectopic Expression; Enzymes; Genes; Genetic; Goals; Homologous Gene; Homologous Protein; Host Defense; Human; Immune; Immune Targeting; Immune response; Immunity; Infection; Inflammatory Response; Innate Immune Response; Interneurons; Invaded; Lead; Light; Link; Mediating; Microbe; Modeling; Molecular; Natural Immunity; Neurofibrillary Tangles; Neurons; Opsonin; Outcome; Parasites; Parasitic infection; Pathogenesis; Patients; Physiological; Play; Production; Proteins; Receptor Cell; Research; Role; Self-Direction; Senile Plaques; Signal Transduction; Surface; System; Testing; Tissues; Venoms; Virulence; Virulence Factors; Wasps; Work; abeta accumulation; age related; antimicrobial peptide; beta-site APP cleaving enzyme 1; cell growth regulation; cytotoxicity; egg; fly; genetic analysis; human disease; immune function; improved; insight; mutant; nervous system disorder; novel; novel therapeutics; overexpression; pathogen; response

Project Summary Alzheimer’s Disease (AD) is a common neurological disease that results in dementia and affects more than 5.7 million Americans. At a molecular level AD is characterized by the formation of β-amyloid plaques in the interneuronal space and neurofibrillary tangles within neurons. The formation of β-amyloid plaques arises due to the aggregation of the amyloid β (Aβ) peptide, and both soluble Aβ peptides and β-amyloid plaques have been linked to cytotoxicity and AD pathogenesis. Despite these clear links to AD, the normal physiological role of Aβ is incompletely understood. Recent research suggests that Aβ plays a role in the innate immune response to infection, and accordingly pathogen infection has been associated with increased levels of Aβ and the subsequent formation of β-amyloid plaques. The goal of the proposed research is to test the link between Aβ and innate immune responses using the Drosophila melanogaster-parasitoid wasp model system. In this system, Drosophila are infected by wasps and mount a genetically conserved cellular innate immune response to kill the invading parasite. Preliminary studies show that loss the Aβ precursor protein APPL blocks the production of a successful immune response, suggesting that the role of Aβ in host defense is evolutionarily conserved. Specific Aim 1 will further define the roles of Aβ, APPL and the APPL processing enzyme BACE in the innate immune response. Notably, the overexpression of human Aβ in Drosophila leads to an infection dependent autoimmune response, in which Aβ appears to target immune cells against self tissue, leading to immune induced tissue damage. Specific Aim 1 will also provide insight into the role of Aβ in the production of this self directed immune damage, including characterizing the localization of Aβ during the immune response and identifying the immune cell receptors that are responding to Aβ expression. Additionally, during infection the parasitoid wasps transfer venom proteins into the Drosophila host. This venom contains virulence factors that allow the parasite to overcome the host immune response. Two parasitoid wasp species have been identified that block the self directed immune damage mediated by Aβ expression, suggesting that they utilize venom virulence proteins that target Aβ. Specific Aim 2 will characterize this activity and identify the Aβ inhibitory proteins found in parasite venom. This proposal will provide insight into the relationship between Aβ and innate immunity and may help uncover novel targets for the treatment of AD.

项目摘要 阿尔茨海默氏病（AD）是一种常见的神经系统疾病，会导致痴呆，并影响更多 分子水平的570万美国人的特征是形成 神经元内的神经元空间和神经纤维状缠结。 由于淀粉样蛋白（Aβ）肽的聚集，并且两个可溶性Aβ-淀粉样木质斑块 与细胞毒性和AD发病机理有关。 Aβ的生理作用不完全理解。 对感染的先天免疫反应，因此病原体感染与增加 Aβ的水平和β-淀粉样斑块的亚分离形成。 Aβ与先天免疫应对剂之间使用果蝇Melanogaster-Propasitoid WASP模型之间的联系 系统。 对入侵寄生虫的免疫反应。 APPL阻止了成功免疫反应的产生，这表明Aβ在宿主防御IS IS IS中的作用 进化保守的目标1将进一步定义Aβ，Appl的作用 先天免疫反应中的酶灯泡。 依赖于依赖的自身免疫反应，其中Aβ似乎靶向免疫细胞反对自我 组织，导致免疫诱导的组织损伤。 自定向免疫损伤的产生，包括表征Aβ在 免疫反应并鉴定对Aβ表达反应的免疫细胞受体。 在感染过程中，寄生虫黄蜂转移到果蝇中 允许寄生虫克服宿主免疫反应的病毒因子。 已经确定了阻止Aβ表达介导的自定向免疫损伤 他们使用毒力蛋白靶Aβ。 在寄生虫中发现的Aβ抑制蛋白。 Aβ和先天免疫力可能有助于发现新的AD治疗靶标。