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 阿尔茨海默病(AD)是一种常见的神经系统疾病，会导致痴呆症，并影响更多 超过570万美国人。在分子水平上，AD的特征是在脑内形成β-淀粉样斑块 神经元内的神经元间隙和神经原纤维缠绕在一起。出现β-淀粉样斑块的形成 由于淀粉样蛋白β(Aβ)多肽以及可溶性Aβ多肽和β-淀粉样斑块的聚集 已被认为与细胞毒性和阿尔茨海默病发病有关。尽管与AD有这些明确的联系，但正常的 Aβ的生理作用还不完全清楚。最近的研究表明，Aβ在 对感染的先天免疫反应，以及相应的病原体感染与 Aβ水平和随后β-淀粉样斑块的形成。这项拟议研究的目标是测试 利用果蝇-黑腹寄生蜂模型研究A-β与先天免疫反应之间的联系 系统。在这个系统中，果蝇被黄蜂感染，并登上遗传保守的固有细胞 杀死入侵寄生虫的免疫反应。初步研究表明，Aβ前体蛋白的丢失 β阻止了成功的免疫反应的产生，这表明APPL在宿主防御中的作用是 进化上保守的。具体目标1将进一步定义Aβ、APPL和APPL处理的作用 BACE酶在先天性免疫反应中的作用。值得注意的是，人类Aβ在果蝇中的过表达导致 对感染依赖的自身免疫反应，在这种反应中，β似乎针对自身的免疫细胞 组织，导致免疫诱导的组织损伤。具体目标1还将深入了解Aβ在 这种自我定向免疫损伤的产生，包括表征Aβ在 免疫反应和识别对Aβ表达有反应的免疫细胞受体。另外， 在感染期间，寄生蜂将毒液蛋白转移到果蝇宿主体内。这种毒液含有 允许寄生虫战胜宿主免疫反应的毒力因子。两种寄生蜂 已经发现可以阻断Aβ表达介导的自我定向免疫损伤，这表明 他们利用针对Aβ的毒力蛋白。具体目标2将描述这一活动的特点并确定 一种在寄生虫毒液中发现的β抑制蛋白。这项提案将提供对两国关系的洞察 Aβ和先天免疫，并可能有助于发现治疗AD的新靶点。