Copper Homeostasis and APP-induced Neurodegeneration in Drosophila

阿尔茨海默病S病是一种许多老年人患有的衰弱的神经退行性疾病，其特征是受影响患者的大脑中存在异常的蛋白质积累，称为斑块。斑块含有淀粉样蛋白，也含有大量的必需金属铜和锌。铜是形成这些蛋白质聚集体所必需的，并增加了淀粉样蛋白的毒性效应，这导致了铜结合化学物质可以用于治疗阿尔茨海默病的想法。然而，在动物模型上的实验产生了相互矛盾的结果，一些人认为铜水平的增加可以保护神经元免受损伤，而另一些人则声称相反的效果。由于使用了不同的实验系统，这些研究的比较受到了阻碍。我们将使用一个简单的昆虫模型--果蝇黑腹果蝇来阐明铜在阿尔茨海默病进展中的作用。果蝇神经组织中淀粉样蛋白的产生会产生与人脑相似的神经退化效应，但只需几周时间，而不是人类所需的几年时间。我们将结合淀粉样蛋白的产生和铜吸收和输出蛋白的产生来研究铜水平变化的影响。我们还将测试增加饮食中铜和其他金属的影响，以确定饮食水平是否是疾病进展的重要因素。最后，我们将使用果蝇模型来测试大量的金属结合化合物和药物，以减缓或阻止淀粉样蛋白产生造成的神经元损伤，确定治疗阿尔茨海默病的潜在疗法。这项工作将对铜在阿尔茨海默病S病发展过程中的作用提供至关重要的、明确的澄清，并可能导致这种疾病的新疗法的开发，该疾病正迅速成为发达国家的一个主要社会和经济问题。

Alzheimer s disease, a debilitating neurodegenerative disorder suffered by many of our elderly, is characterised by the presence of abnormal protein accumulations called plaques in the brains of affected patients. Plaques contain amyloid protein and also have high levels of the essential metals copper and zinc. Copper is needed for the formation of these protein aggregations and increases the toxic effects of amyloid, leading to the idea that copper-binding chemicals could be used to treat Alzheimer s disease. However experiments in animal models have produced conflicting results, some suggesting that increased copper levels protect against neuronal damage while others claim the opposite effect. Comparison of these studies is hampered by the different experimental systems used. We will clarify the role of copper in the progression of Alzheimer s disease using a simple insect model, the fly Drosophila melanogaster. Production of amyloid in Drosophila neuronal tissues produces a neurodegenerative effect similar to that seen in human brains, but in a matter of weeks rather than the years required in humans. We will combine production of amyloid with production of copper uptake and export proteins to investigate the effect of changing copper levels. We will also test the effect of increasing copper and other metals in the diet to see whether dietary levels are an important factor in disease progression. Finally, we will use the Drosophila model to test large numbers of metal binding compounds and drugs for ones that slow or halt the neuronal damage caused by amyloid production, identifying potential therapeutics for the treatment of Alzheimer s disease. This work will provide a vital and definitive clarification of the role of copper in the progression of Alzheimer s disease and potentially lead to the development of novel treatments for this disease that is rapidly becoming a major social and economic problem in the developed world.