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

阿尔茨海默病(AD)是一种无法治愈的神经退行性大脑疾病，会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。它的特点是两者并存 细胞外淀粉样斑块，主要由淀粉样β-42(Abeta)多肽形成，以及细胞内 含有异常tau聚集体的神经原纤维缠结。Abeta和tau被认为是不相连的 多年来一直是罪魁祸首，但根据最近的研究，很明显，他们有密切的联系和拥有 协同活动。遗憾的是，人们对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方法的发展。为了解决这个问题，我们创造了一个新的苍蝇模型 AD的基因同时产生人类Abeta和tau，导致协同病理。这些苍蝇展示了 Abeta的细胞外沉积，病理性tau的细胞内聚集，以及进行性神经变性。 我们的初步数据显示，这些苍蝇的强大和一致的病理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来对第一个大的 收集表达人类基因的转基因果蝇。该集合包括许多AD风险基因，已识别 通过基因组广谱关联研究(GWAS)或下一代测序(NGS)，它们在 人们对这种疾病知之甚少。因此，我们将把我们的Abeta+tau果蝇与1500个菌株杂交，这些菌株被设计成 特异性地激活具有相似表达水平的人HA标记的cDNA。我们将首先在苍蝇眼中测试它们， 这提供了一个有用且易于评分的表型来评估共表达每个人类基因的效果 Abeta和tau(目标1)。然后，我们将验证较强的抑制者是否有能力改变 用细胞、组织学和行为学方法研究苍蝇脑的神经病理学(目标2)。我们强烈要求 相信这个新的和独特的库的屏幕将导致快速识别相关的点击调解 Abeta和tau之间的病理性相互作用，并将揭示一系列关键的人类靶点 翻译研究。因此，这项工作可能大大有助于实现《国家计划》的目标 阿尔茨海默氏症。

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.