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

家族性阿尔茨海默病表型修饰基因的鉴定和表征

• 批准号: nhmrc : 276401
• 负责人: A/Pr John Kwok
• 金额: $ 27.56万
• 依托单位: Garvan Institute of Medical Research
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2004
• 资助国家: 澳大利亚
• 起止时间: 2004-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/identification-characterisation-phenotypic-alzheimers-disease/76517
• 关键词: Identification; characterisation; phenotypic; modifier; genes

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.

阿尔茨海默病（AD）是导致痴呆症的最常见原因，也是第四大常见死亡原因。阿尔茨海默病没有有效的治疗方法，目前可用的药物在延缓这种不可避免的致命疾病的发病和进展方面的价值非常有限。阿尔茨海默病的诊断依据是大脑中的两个关键特征，即由淀粉样蛋白-肽组成的致密斑块和由tau蛋白组成的缠结。新的治疗靶点的发现，如产生β淀粉样蛋白肽的酶，以及与这些靶点相互作用的药物的开发，为开发延缓疾病发作、延缓甚至停止这种无情进展性疾病的发展提供了前景。我们的研究重点是与不同形式的阿尔茨海默病有关的基因。我们和其他人描述的一种神经病理变异形式的特征是大的弥漫性（棉絮）淀粉样斑块。棉絮斑块病理与AD引起早老素1 （PS-1）基因突变有关。我们描述的另一种临床AD变体的特征是存在痉挛性麻痹（SP）。SP与PS-1突变相关，但存在时延迟疾病发病。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絮斑块的产生或修饰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遗传方法克隆修饰基因，并评估它们对阿尔茨海默病的临床和病理发展的影响。通过研究在这些不同形式的阿尔茨海默病中改变PS-1突变的基因的作用，我们希望能更好地了解斑块和缠结实际上是如何导致疾病的临床症状的，并获得治疗阿尔茨海默病的新方法的见解。