阿尔茨海默病（AD）是一种渐进性中枢神经变性型疾病，并伴有由淀粉样蛋白β多肽在细胞外形成老年斑等神经病理学方面的损害。Aβ是淀粉样前体蛋白（APP）异常裂解的产物，其表达水平对淀粉样蛋白多肽的形成和在神经组织中的沉积有着密切的关系。本项目拟研究APP基因表达的转录调控，将采取含有APP启动子的萤火虫荧光素酶的报告质粒在神经母细胞瘤U87MG细胞中的转录活性分析的方法来探讨人转录活化因子Purα对APP基因负调控的机制，并通过Pur α和Egr-1蛋白的相互作用的研究分析，以期阐明Purα对APP蛋白表达的调控作用的机制，并进一步探讨蛋白与蛋白，蛋白与核酸之间的相互作用， 揭示转录因子Pur α在调控蛋白表达过程中的作用机制，从而为AD的防治提供一条新途径。同时通过对DNA-蛋白，蛋白-蛋白相互作用的研究，进一步探索基因表达的调控方面的机制，为AD的治疗提供新的思路。

The Alzheimer's disease was first described in 1906 and was identified as an ''unusual disease of the cerebral cortex'', which caused memory loss, disorientation, hallucinations. The most important hallmark in Alzheimer's disease study was the establishment of amyloid hypothesis (Amyloid beta, A beta). The A beta aggregates on the CNS to form the senile plaque which disrupts the brain cells, clogs the points of cell-to-cell communications,activates immune cells that trigger the inflammation and devours the disable cells and ultimately, kills cells. In our previous study, we found that the Pur a protein can down-regulate the amyloid precursor protein (APP) promoter activity. In order to better understand the mechanism of this negative regulation of Pur alpha, we use the luciferase contructs which contains the APP promoter, to checked the transcriptional regulation of Pur alpha on APP gene expression through the analysis of transcriptional activation. We focus the target on the 5'UTR where the predicted APP binding site and Egr-1 binding site are overlapped. We promote a hypothesis that the regulational effects of Pur alpha on APP promoter is completed through another transcriptiona factor, Egr-1, which was proved to be a positive rehulational factor on APP promoter in our previous studies.Since the binding sites of these two proteins on APP promoter is overlapped,there might be a displacement mechnism for the regulation of APP gene expression. In order to prove our hypothesis, we put the stress on the interaction of the two proteins. A serious approches will be employed to study the physical interactions of these two proteins in vitro and in vivo, also the functional interaction will also be evaluated.The experiment will be set as following steps, first to confirm the physical binding site of these two proteins on APP promoter 5'UTR area and the thranscriptional activity will be assessed by the luciferase activity analysis,appropriate mutations will be created to confirm the function of the binding and also, the EMSA, CHIP's assay and DNA foot proting approches will be used for the further confimation.Second the interaction of these two proteins will be evaluated through a series approches including the pull down assay and co-IP/wester, colocalization as well as the subcellular distributions of the two proteins, the functional interaction domain will be assessed through the series deletions of the Pur alpha and Egr-1; Last step will be engaged the changes of Amyloid peptide within the cells and the effects of Pur alpha on secretase and apopain,cell cycle and cyclins will be also evaluated. Above all, we will explain the mechanism by which the Pur alpha regulate the APP gene expression privide the clues for the treatment of AD.