Alzheimer's disease and related disorders: Mechanism of tau pathology in established and novel transgenic animal models

阿尔茨海默病及相关疾病：已建立和新型转基因动物模型中 tau 蛋白病理学机制

• 批准号: nhmrc : 402596
• 负责人: Prof Jurgen Gotz
• 金额: $ 28.21万
• 依托单位: The University of Sydney
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2006
• 资助国家: 澳大利亚
• 起止时间: 2006-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/alzheimers-disease-related-animal-models/97051
• 关键词: Alzheimer; disease; related; disorders; Mechanism

Alzheimer's disease (AD) is a devastating neurodegenerative disease for which no cure is available. It affects more than 15 million people worldwide. There are estimates that by 2040, approximately 500'000 Australians will suffer from AD, with associated health costs of about 3% of the GDP. AD is characterized by two major brain lesions, beta-amyloid plaques and neurofibrillary tangles (NFTs). The latter contain a protein called tau which is in a fibrillar and highly phosphorylated state. We were the first to establish a transgenic animal model of pre-tangles and, together with Dr. Hutton's laboratory, of NFT formation. We could further show that injections of beta-amyloid into brains of our tau mutant mice enhanced the NFT pathology in these mice. By Functional Genomics we identied genes and proteins, which are induced by tau expression. The specific aim of this proposal is to determine whether oxidative stress enhances the tau pathology in our tau mutant mice and whether distinct brain areas are particularly susceptible to this kind of stress. The reason for addressing this question is twofold: On the one hand, we have found in our mice that reactive oxygen species are increased, secondly it is known that some brain areas in the AD brain are degenerating, whereas others are not. A second aim is to develop novel tau transgenic models where individual interactions of tau with cellular proteins are disturbed. Finally, we want to determine whether the two kinases BMX and FAK and the phosphatase PPV regulate tau phosphorylation in vivo. Together, we hope that our efforts lead to a better understanding of the pathogenic mechanisms in AD and related disorders. As pathocascades are likely to be shared between a range of diseases, these findings may also contribute to other fields of research, such as Parkinson's disease. Ultimately, these efforts will assist in the development of a safe treatment of AD.

阿尔茨海默病（AD）是一种毁灭性的神经退行性疾病，目前尚无治愈方法。它影响到全世界1500多万人。据估计，到2040年，约有50万澳大利亚人将患有AD，相关的医疗费用约占GDP的3%。AD的特征在于两种主要的脑病变，β-淀粉样蛋白斑块和神经纤维缠结（NFT）。后者含有一种称为tau的蛋白质，它处于纤维状和高度磷酸化状态。我们与赫顿博士的实验室一起建立了预缠结的转基因动物模型，并建立了NFT形成的转基因动物模型。我们可以进一步证明，将β-淀粉样蛋白注射到我们的tau突变小鼠的大脑中，增强了这些小鼠的NFT病理学。通过功能基因组学，我们鉴定了tau蛋白表达诱导的基因和蛋白。这项提议的具体目的是确定氧化应激是否会增强我们的tau突变小鼠的tau病理学，以及不同的脑区是否特别容易受到这种应激的影响。解决这个问题的原因有两个：一方面，我们在小鼠中发现活性氧增加，其次，已知AD大脑中的一些脑区正在退化，而其他脑区则没有。第二个目标是开发新型tau转基因模型，其中tau与细胞蛋白的个体相互作用受到干扰。最后，我们想确定两种激酶BMX和FAK以及磷酸酶PPV是否在体内调节tau蛋白磷酸化。总之，我们希望我们的努力能够更好地了解AD和相关疾病的致病机制。由于一系列疾病之间可能存在共同的病理级联，这些发现也可能有助于其他领域的研究，如帕金森病。最终，这些努力将有助于开发AD的安全治疗方法。