Identification and characterisation of phenotypic modifier genes in familial Alzheimer's disease

阿尔茨海默病(AD)是痴呆症最常见的原因，是第四大最常见的死亡原因。目前尚无有效的治疗阿尔茨海默病的方法，目前可用的药物在延缓这种总是致命的疾病的发病和进展方面的价值非常有限。AD的诊断依据是大脑中的两个关键特征，即由淀粉样β蛋白组成的致密斑块和由tau蛋白组成的缠结。新的治疗靶点的确定，如产生淀粉样β多肽的酶，以及与这些靶点相互作用的药物的开发，为开发延缓疾病发病、延缓甚至阻止这种持续进行性疾病的发展的治疗方法提供了前景。我们的研究重点是与各种形式的阿尔茨海默病相关的基因。我们和其他人描述的一种神经病理变异型的特征是大的弥漫性(棉花)淀粉样斑块。棉花斑块病理与导致早老素1(PS-1)基因突变的AD有关。我们已经描述的另一个临床AD变异体的特征是痉挛性瘫痪(SP)的存在。SP与PS-1突变有关，但当存在时会延迟疾病的发生。我们已经确定了两个潜在的修饰基因，它们可能直接参与棉毛斑块的产生，或者改变PS-1突变的影响和SP的发生。对于这两个基因，本项目的目标是使用一系列的遗传方法来克隆修饰基因，并评估它们对阿尔茨海默病临床和病理发展的影响。通过研究在这些不同形式的AD中改变PS-1突变影响的基因的作用，我们希望对斑块和缠结实际上如何导致疾病的临床症状有更多的了解，并对治疗AD的新方法有更深入的了解。

Alzheimer's disease (AD) is the most common cause of dementia the fourth most common cause of death. There are no effective cures for AD and those drugs currently available are of very limited value in delaying the onset and progression of this invariably fatal disease. AD is diagnosed by two key features in the brain, dense plaques composed of the amyloid beta peptide, and tangles composed of the tau protein. The identification of new therapeutic targets, such as the enzymes which produce amyloid beta peptide, and the development of drugs that interact with these targets offers the prospect of developing treatments to delay disease onset, retard or even halt the development of this relentlessly progressive disease. Our research focuses on the genes that are involved in variant forms of AD. One neuropathological variant form we and others have described is characterised by large diffuse (cotton wool) amyloid plaques. Cotton wool plaque pathology is associated with AD causing mutations in the presenilin 1 (PS-1) gene. Another clinical AD variant that we have described is characterised by the presence of spastic paraparesis (SP). SP is associated with PS-1 mutations, but when present delays disease onset. We have identified two potential modifier genes which are likely to be directly involved in the production of cotton wool plaques or modifying the effect of PS-1 mutations and the occurence of SP. For both genes, the goal of this project is to use a range of genetic approaches to clone the modifier genes by and to assess their effects on the clinical and pathological development of AD. By studying the effects of genes which act to modify the effects of the PS-1 mutations in these variant forms of AD we hope to gain a greater understanding of how the plaques and tangles actually lead to the clinical symptoms of the disease and to gain insights into new ways in which AD may be treated.