Functional assessment of 1,500 human genes against coexistent Abeta and tau pathology in vivo

阿尔茨海默氏病（AD）是一种无法治愈的神经退行性脑疾病，导致进行性记忆丧失 和认知能力下降，是痴呆症最常见的形式。其特点是： 细胞外淀粉样斑块，主要由淀粉样β-42（Abeta）肽形成，和细胞内淀粉样斑块， 含有异常tau聚集体的神经元缠结。认为Abeta和tau不相关 多年来一直是罪魁祸首，但鉴于最近的研究，很明显，他们是密切相关的，并拥有 协同活动。可悲的是，关于Abeta和tau相互作用如何触发AD发病机制知之甚少， 这严重阻碍了有效治疗的发展。为了解决这个问题，我们创建了一个新的苍蝇模型， 在遗传上产生人Abeta和tau两者，导致协同病理学的AD。这些苍蝇展示 A β的细胞外沉积、病理性tau的细胞内聚集和进行性神经变性。 我们的初步数据表明，这些苍蝇的稳健和一致的病理学代表了一个理想的平台， 用于基因发现计划。因此，我们建议使用这些苍蝇功能评估第一个大的 表达人类基因的转基因果蝇的集合。该集合包括许多AD风险基因， 通过全基因组关联研究（GWAS）或下一代测序（NGS），其在 人们对这种疾病知之甚少。因此，我们将把Abeta+tau果蝇与1,500株基因工程菌株杂交， 特异性激活具有相似表达水平人HA标记的cDNA。我们将首先在蝇眼中测试它们， 它提供了一个有用的和易于评分的表型，以评估共表达每个人类基因的效果， 与Abeta和tau（Aim 1）。然后，我们将验证更强的抑制因子是否有能力改变 使用细胞、组织学和行为学方法研究果蝇脑的神经病理学（目的2）。我们强烈 我相信，这个新的和独特的图书馆屏幕将导致相关命中介导的快速识别 研究Abeta和tau之间的病理相互作用，并将揭示一系列关键的人类靶点， 翻译研究因此，这项工作可能会大大有助于实现《国家消除贫穷计划》的目标， 老年痴呆症

Alzheimer’s disease (AD) is an incurable neurodegenerative brain disorder that causes progressive memory loss and cognitive decline, and is the most common form of dementia. It is characterized by the coexistence of extracellular amyloid plaques, mainly formed by the amyloid beta-42 (Abeta) peptide, and intracellular neurofibrillary tangles containing aggregates of abnormal tau. Abeta and tau were considered as disconnected culprits for many years, but in view of recent studies, it is clear that they are intimately related and possess synergistic activities. Sadly, very little is known about how Abeta and tau interactions trigger AD pathogenesis, which significantly hinders the development of effective treatments. To address this, we created a new fly model of AD that genetically produces both human Abeta and tau resulting in synergistic pathology. These flies display extracellular deposits of Abeta, intracellular aggregation of pathological tau, and progressive neurodegeneration. Our preliminary data show that the robust and consistent pathology of these flies represents an ideal platform for gene discovery initiatives. Therefore, we propose to use these flies to functionally assess the first large collection of transgenic flies expressing human genes. This collection includes many AD risk genes, identified by Genome Wide Association Studies (GWAS) or Next Generation Sequencing (NGS), whose functional role in the disease is poorly understood. Thus, we will cross our Abeta+tau flies with 1,500 strains engineered to specifically activate human HA-tagged cDNAs with similar expression levels. We will first test them in the fly eye, which provides a useful and easy-to-score phenotype to assess the effect of co-expressing every human gene with Abeta and tau (Aim 1). Then, we will validate the stronger suppressors for their ability to alter the course of neuropathology in the fly brain using cellular, histological and behavioral approaches (Aim 2). We strongly believe that the screen of this new and distinctive library will lead to a rapid identification of relevant hits mediating pathological interactions between Abeta and tau, and will unveil a set of key human targets for immediate translational studies. Therefore, this work may contribute significantly to the goals of the National Plan to Address Alzheimer’s Disease.