Functional analysis of glia in tauopathy

阿尔茨海默病是最常见的神经退行性疾病，临床特点是 认知功能障碍。该病的典型神经病理特征包括形成 细胞外淀粉样斑块、异常磷酸化和聚集的tau在神经元内的沉积 蛋白质转化为神经原纤维缠结和胶质细胞增多症。神经胶质病理通常被认为是继发性的， 或者是被动的，改变。然而，最近在理解正常和病理神经胶质生物学方面的进展 相反，这表明神经胶质细胞可能在包括阿尔茨海默病在内的神经疾病中发挥积极作用。 在这里，我们采用遗传学的方法来定义蛋白质和通路，这些蛋白质和通路介导了神经胶质细胞对 阿尔茨海默氏症相关的神经变性。利用先进的分子和遗传工具， 果蝇的短寿命和保守的神经胶质生物学我们将鉴定神经胶质蛋白和途径， 对老化成人大脑中tau神经毒性的影响。在原理研究的证明中，我们验证了一本小说 一种研究非细胞自主性神经变性的系统，并表明我们的检测系统 在公正筛选的背景下工作。此外，根据观察，许多基因 通过全基因组遗传关联研究(GWAS)表达与阿尔茨海默病有关 主要或主要是在胶质细胞中，我们将测试上调和下调这些基因的效果。 在tau诱导的神经毒性中，苍蝇神经胶质细胞中Gwas衍生的候选基因。为了将我们的基因 通过真实人类疾病的模型实验，我们将使用最先进的信息学工具来 将功能基因数据与阿尔茨海默病转录组和蛋白质组学相结合。因为我们的 系统分析将在神经胶质亚型的特定基础上进行我们的研究不仅可以勾勒出神经胶质 调节tau对神经元毒性的网络，但也提供了对新定义的神经胶质细胞的功能洞察 子类型。我们的研究将发展对健康和疾病中神经胶质细胞生物学的基本见解，并将 扩大与阿尔茨海默病治疗发展相关的细胞和分子靶点阵列 以及相关的神经退行性疾病。

Alzheimer's disease is the most common neurodegenerative disorder and is characterized clinically by cognitive dysfunction. Classic neuropathological features of the disease include the formation of extracellular amyloid plaques, intraneuronal deposition of abnormally phosphorylated and aggregated tau protein into neurofibrillary tangles, and gliosis. Glial pathology has generally been considered a secondary, or reactive, change. However, recent advances in understanding normal and pathological glial biology have instead suggested that glia may play an active role in neurological disorders, including Alzheimer’s disease. Here we take a genetic approach to define proteins and pathways mediating the influence of glia on Alzheimer’s-associated neurodegeneration. Taking advantage of the advanced molecular and genetic tools, short lifespan, and conserved glial biology in Drosophila we will identify glial proteins and pathways that can influence tau neurotoxicity in aging adult brains. In proof of principle studies, we have validated a novel system for studying non-cell autonomous neurodegeneration in tauopathy and show that our assay system works in the context of unbiased screening. In addition, based on the observation that many genes implicated in Alzheimer’s disease through genome wide genetic association studies (GWAS) are expressed predominantly or substantially in glial cells, we will test the effect of upregulating and downregulating these GWAS-derived gene candidates in fly glia on tau-induced neurotoxicity. To additionally connect our genetic model experiments with the authentic human disease, we will use state-of-the-art informatics tools to integrate functional genetic data with Alzheimer’s disease transcriptomics and proteomics. Since our systems analysis will be performed on a glial subtype-specific basis our studies can not only outline glial networks modulating the toxicity of tau to neurons, but also provide functional insight into newly defined glial subtypes. Our studies will develop fundamental insights into glia cell biology in health and disease and will expand the array of cellular and molecular targets relevant for therapy development in Alzheimer’s disease and related neurodegenerative disorders.