Down Syndrome and Alzheimer's Disease - determining which chromosome 21 gene or genes when over-expressed modulate Abeta toxicity and accumulation

唐氏综合征（DS）是早发性阿尔茨海默病（AD）的最大危险因素。在过去的几十年里，DS患者的寿命延长增加了该人群的AD负担。患有DS的人携带21号染色体（Hsa 21）的额外拷贝，其编码包括APP在内的234个基因。APP的基因产物被切割成淀粉样蛋白-β（Ab），其在大脑中聚集形成淀粉样蛋白斑块，这是早期AD的特征。已证明APP单独复制足以导致早发性AD，这表明该基因在增加DS患者AD风险方面起着至关重要的作用。然而，其他Hsa 21基因重复对AD风险的贡献尚不清楚。Wiseman等人，最近证明，在小鼠模型中，除APP以外的HSA 21基因的三倍增加了AD病理学的风险。具体而言，发现39个Hsa 21直向同源物的区域足以加剧小鼠中的Ab聚集和认知下降。在这个项目中，我想确定和验证Hsa 21基因（S）负责观察到的AD风险增加的结果，他们的三体。根据NC 3Rs在研究中减少、替代和改进动物使用的原则，我将使用果蝇（Drosophila melanogaster）来研究我们的研究问题，取代对小鼠模型的需求。这将使我能够过度表达每一个候选基因，以评估它们对果蝇大脑中Abtoxicity和积累的影响。此外，我的目标是确定的临床相关性的基因，通过使用人类遗传和临床数据集收集的LonDownS财团和神经病理学研究死后的大脑材料。这项研究将进一步加深我们对DS背景下AD病理学的理解，并可能有助于开发针对早发性AD患者的新疗法。

Down Syndrome (DS) is the greatest risk factor for early-onset Alzheimer's disease (AD). Over the last decades, greater longevity of people with DS has increased the burden of AD in this population. People with DS carry an extra copy of chromosome 21 (Hsa21), which encodes 234 genes including APP. The gene product of APP is cleaved into amyloid-beta (Ab), which aggregates in the brain to form amyloid plaques, characteristic of early AD. Duplication of APP alone has been shown to be sufficient to cause early-onset AD, suggesting a crucial role of this gene in increasing the risk of AD for people with DS. However, the contribution of other Hsa21 gene duplications to AD risk is not yet understood. Wiseman et al., recently demonstrated that the triplication of HSa21 genes other than APPincreases the risk of AD pathology in mouse models. Specifically, a region of 39 Hsa21 orthologues was found to be sufficient to exacerbate Ab aggregation and cognitive decline in mice. In this project, I want to identify and characterise the Hsa21 gene(s) responsible for the observed increase in AD risk as a result of their trisomy. In line with NC3Rs' principles of reducing, replacing and refining the use of animals in research, I will be investigating our research question using the fruit fly Drosophila melanogaster, replacing the need for mouse models. This will allow me to over-express each of the candidate gene in turn to assess their effects on Abtoxicity and accumulation in the fly brain. In addition, I aim to determine the the clinical relevance of the genes identified by using human genetic and clinical data sets collected by the LonDownS consortium and neuropathological studies of post-mortem brain material. This research will further our understanding of AD pathology in the context of DS and may contribute to the development of novel therapies for people with early-onset AD.