Functional characterisation of newly identified Alzheimer's Disease associated genes in human and invertebrate model systems

阿尔茨海默病是痴呆症最常见的形式，是一种神经疾病，会导致记忆和认知能力的严重丧失。阿尔茨海默病的症状是由大脑中神经细胞的进行性死亡引起的。阿尔茨海默病患者大脑中神经元的退化伴随着大脑中“淀粉样蛋白”的积聚。随着神经元的死亡和淀粉样蛋白的积累，特殊的“小胶质”细胞--一种从大脑中清除废物的免疫细胞--被激活，本身可能进一步导致神经元的死亡。阿尔茨海默氏症通常被发现是家族遗传的。这一观察表明，个体基因组中编码的DNA基因可能有助于患上这种疾病的易感性。为了了解基因是如何导致阿尔茨海默氏症的，大型“全基因组关联研究”(Gwas)对数万名痴呆症患者和非痴呆症患者的DNA进行了比较。这些研究非常有洞察力，确定了数十个与阿尔茨海默病易感性增加有关的基因。了解这些基因如何改变神经元和小胶质细胞的健康和功能是阿尔茨海默病研究领域目前面临的挑战之一，特别是由于新易感基因的发现速度。我们的项目将重点放在与阿尔茨海默病易感性增加有关的新基因清单上。欧洲阿尔茨海默病DNA生物库(EADB)是迄今为止规模最大的GWAS研究--确定了75个与阿尔茨海默病有关的基因，其中42个是新发现的。为了快速测试这些新基因可能如何导致阿尔茨海默氏症，我们正在转向一个非常强大的实验模型系统：果蝇。尽管苍蝇很小，但它有一个复杂的大脑，可以复制阿尔茨海默病患者的许多症状和病理。此外，苍蝇基因组与人类基因组有许多相似之处，包含许多与阿尔茨海默病有关的基因。利用对果蝇的基因操作，我们将测试EADB研究确定的基因如何加剧或抑制阿尔茨海默病的特征，包括行为、寿命和淀粉样蛋白在大脑中积累的变化。我们将利用这些苍蝇实验来识别EADB研究中强烈修改阿尔茨海默病病理特征的基因。为了进一步了解这些基因如何增加人类患阿尔茨海默病的风险，我们接下来将在人类神经元和小胶质细胞的最先进细胞培养中测试从我们的苍蝇实验中确定的最优先基因。我们将培养神经元和小胶质细胞的细胞，这些细胞已经被基因工程改造，以复制EADB研究确定的人类基因的变化。我们将结合显微图像分析、分子生物学技术和电生理记录，定义我们优先考虑的阿尔茨海默病易感基因如何改变神经元的活动。对于小胶质细胞，我们将测试阿尔茨海默病易感基因如何促进这些特殊细胞的免疫反应和废物处理活动。我们的创新项目将汇集人类遗传学家、苍蝇生物学家和人类细胞培养研究团队的专业知识，以快速识别和了解新基因如何与阿尔茨海默病有关。最终，我们的目标是更好地了解这些基因如何改变神经元和神经胶质细胞的功能，使人们更容易患上阿尔茨海默病。提高我们对阿尔茨海默病遗传学的理解将支持未来的研究，即我们如何利用这些基因来设计治疗痴呆症的新疗法。

Alzheimer's disease is the most common form of dementia, a neurological disorder which causes profound loss of memory and cognitive ability. The symptoms of Alzheimer's disease are caused by progressive death of neuronal cells in the brain. The degeneration of neurons in the brains of people affected by Alzheimer's disease is accompanied by the build-up of 'amyloid' protein in the brain. As neurons die and amyloid protein accumulates, specialised 'microglia' cells - a type of immune cell that clears away waste material from the brain - become activated and may themselves further contribute to the death of neurons. Alzheimer's disease is often found to be inherited within families. This observation suggests DNA genes encoded within an individual's genome may contribute to susceptibility of developing the disorder. In an effort to understand how genes can contribute to Alzheimer's disease, large 'genome wide association studies' (GWAS) have compared the DNA of tens of thousands of people with and without dementia. These studies have been remarkably insightful, identifying many dozens of genes that are linked to increased susceptibility of developing Alzheimer's disease. Understanding how these genes alter the health and function of neurons and microglia is one of the current challenges in the Alzheimer's Disease research field, particularly due to the rate of discovery of new susceptibility genes. Our project will focus on a new list of genes linked to increased susceptibility to developing Alzheimer's disease. The European Alzheimer DNA BioBank (EADB) is the largest GWAS study to date - identifying 75 genes linked to Alzheimer's disease of which 42 are new discoveries. To rapidly test how these new genes might contribute to Alzheimer's disease, we are turning to a remarkably powerful experimental model system: fruit flies. Thought small, flies have a complex brain which can replicate many of the symptoms and pathologies of people living with Alzheimer's disease. Furthermore, the fly genome shares much similarity with the human genome, containing many of the genes linked to Alzheimer's disease. Using genetic manipulation of fruit flies we will test how the genes identified by the EADB study aggravate or suppress features of Alzheimer's disease, including changes in behaviour, lifespan and amyloid protein build up in the brain.We will use these fly experiments to identifying genes from the EADB study that strongly modifying features of Alzheimer's disease pathology. To further our understanding of how these genes increase risk of humans developing Alzheimer's disease, we will next test the highest priority genes identified from our fly experiments in state-of-the-art cell cultures of human neurons and microglia. We will grow cell cultures of neurons and microglia that have been genetically engineered to replicate the changes in human genes identified by the EADB study. We will define how our prioritised Alzheimer's disease susceptibility genes alter the activity of neurons, using a combination of microscopy image analysis, molecular biology techniques and electrophysiological recording. For microglia, we will test how Alzheimer's disease susceptibility genes contribute to immunity responses and waste disposal activity of these specialised cells.Our innovative project will bring together the expertise of human geneticists, fly biologists and human cell culture research teams to rapidly identify and understand how novel genes contribute to Alzheimer's disease. Ultimately we aim to better understand how these genes alter the function of neuron and glia cells to render people more vulnerable to developing Alzheimer's disease. Advancing our understanding of the genetics of Alzheimer's disease will support future studies into how we may exploit these genes to design novel therapeutics for the treatment of dementia.