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

项目摘要 阿尔茨海默病（AD）是一种常见的神经系统疾病，导致痴呆， 超过570万美国人。在分子水平上，AD的特征在于在细胞中形成β-淀粉样蛋白斑块。 神经元内的神经元间隙和神经纤维缠结。β-淀粉样蛋白斑块的形成 由于淀粉样β（Aβ）肽的聚集，可溶性Aβ肽和β-淀粉样斑块 与细胞毒性和AD发病机制有关。尽管这些与AD有明显的联系，但正常的 Aβ的生理作用尚未完全了解。最近的研究表明，Aβ在 对感染的先天免疫应答，因此病原体感染与增加的 Aβ水平和随后的β-淀粉样斑块的形成。这项研究的目的是测试 利用果蝇-拟寄生蜂模型研究Aβ与先天免疫应答之间的联系 系统在这个系统中，果蝇被黄蜂感染，并安装一个遗传保守的细胞先天 免疫反应杀死入侵的寄生虫。初步研究表明，Aβ前体蛋白的缺失 APPL阻断成功免疫应答的产生，表明Aβ在宿主防御中的作用是 进化上保守。具体目标1将进一步定义Aβ、APPL和APPL加工的作用 BACE酶在先天免疫反应中的作用。值得注意的是，人类Aβ在果蝇中的过度表达导致了 感染依赖性自身免疫反应，其中Aβ似乎靶向免疫细胞， 组织，导致免疫诱导的组织损伤。具体目标1还将提供对Aβ在以下方面的作用的深入了解： 这种自我导向的免疫损伤的产生，包括表征Aβ在免疫过程中的定位。 免疫反应和识别对Aβ表达有反应的免疫细胞受体。此外，本发明还 在感染过程中，寄生蜂将毒液蛋白质转移到果蝇宿主中。这种毒液含有 毒力因子，使寄生虫克服宿主的免疫反应。两种寄生蜂 已经鉴定出阻断由Aβ表达介导的自身定向免疫损伤，这表明 它们利用针对Aβ的毒液毒力蛋白。具体目标2将描述这一活动的特点，并确定 在寄生虫毒液中发现的Aβ抑制蛋白。该提案将深入了解以下方面的关系： Aβ和先天免疫，并可能有助于发现治疗AD的新靶点。

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.