In Search of the Molecular Basis of Memory Loss in Tauopathy

描述（由申请人提供）：本提案的目的是研究在tau蛋白病中发生神经元损失之前发生的脑功能恶化，tau蛋白病是一组涉及tau蛋白的神经退行性疾病，包括阿尔茨海默病，通过具体解决以下问题： 以下基本问题：tau蛋白病记忆丧失的分子基础是什么？我们表明，神经元缠结，阿尔茨海默病的主要神经病理学特征，对认知功能障碍的贡献很小（SantaCruz等人，Science，2005）。这项工作使我们相信，一种未知的tau蛋白的后修饰形式是负责的，我们在当前的申请中提出鉴定这种实体，我们称之为tau*（tau星星）。我们在大脑中发现了一种淀粉样蛋白（A）蛋白的后修饰形式，称为A *56（A beta星星56），当注射到正常动物中时会导致记忆丧失（Lesn <$et al.，Nature，2006）。A的发现 *56是第一次用于识别传染病病原体的原则已被应用于确定非传染性神经退行性疾病中认知功能障碍的病因。如果我们获得尤里卡奖，这种方法是否可以扩展到tau蛋白和tau蛋白病是我们将面临的挑战。这项工作不仅将为思考如何处理神经退行性疾病问题铺平新的道路，而且还将引导研究工作，以了解参与阿尔茨海默病发病机制的分子物种。如果我们要为这种疾病开发合理和机械的治疗方法，那么了解这种发病机制显然是至关重要的，这种疾病目前影响着500万美国人，到2050年可能达到1600万。公共卫生相关性：本提案的目的是确定tau蛋白病记忆丧失的分子基础。我们认为，记忆丧失是由一种未知的tau蛋白的后修饰形式引起的，我们称之为tau*（tau星星）。为了找到tau*，我们将采用允许识别传染病病原体的原则，其中包括识别与记忆丧失相关的候选tau种类，分离这些种类，并将其应用于神经元和小鼠实验系统以测定其生物活性。

DESCRIPTION (provided by applicant): The objective of this proposal is to study the deterioration in brain function that takes place before neuronal loss occurs in tauopathy, a group of neurodegenerative disorders involving the tau protein that includes Alzheimer's disease, by specifically addressing the following basic question: What is the molecular basis of memory loss in tauopathy? We showed that neurofibrillary tangles, a cardinal neuropathological feature of Alzheimer's disease, contributed very little to cognitive dysfunction (SantaCruz et al., Science, 2005). This work led us to believe that an as yet unknown post-translationally modified form of the tau protein is instead responsible, and we propose in the current application to identify this entity, which we call tau* (tau star). We discovered a post-translationally modified form of the amyloid-¿ (A¿) protein in the brain, called A¿*56 (A beta star 56), that causes memory loss when injected into normal animals (Lesn¿ et al., Nature, 2006). The discovery of A¿*56 is the first time that the principles used to identify etiological agents of infectious diseases have been applied to determine the etiology of cognitive dysfunction in a non-infectious neurodegenerative disorder. Whether this approach can be extended to tau and tauopathy is the challenge we will undertake if we are given a EUREKA award. This work will not only pave a new way to think about how to approach the problem of neurodegenerative diseases, but will also lead the research effort to understand the molecular species involved in the pathogenesis of Alzheimer's disease. Understanding this pathogenesis is clearly central if we are to develop rational and mechanistic therapies for this disorder, which currently affects 5 million Americans and may reach 16 million by the year 2050. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to determine the molecular basis of memory loss in tauopathy. We propose that memory loss is caused by an as yet unknown posttranslationally modified form the tau protein, which we call tau* (tau star). To find tau* we shall adapt the principles that have allowed for the identification of etiological agents of infectious diseases, which include the identification of candidate tau species that correlate with memory loss, the isolation of these species, and their application to neuronal and murine experimental systems to assay their biological activity.