Pharmacological modulation of tau neurotoxicity in vivo

描述（由申请人提供）：目前尚无高效治疗阿尔茨海默病的方法。为了开发用于药物筛选的合适的体内模型，并且为了研究阿尔茨海默病和相关病症的基本发病机制，我们已经基于人tau和Abeta在果蝇果蝇中的表达创建了该病症的模型。我们的模型概括了人类疾病的关键特征。具体来说，当我们在果蝇中表达人类tau蛋白时，我们观察到寿命缩短，行为异常和异常磷酸化tau蛋白的积累。无偏正向遗传筛选揭示了保守的基本病理机制，包括tau蛋白异常磷酸化、氧化应激、有丝分裂后神经元细胞周期再激活和肌动蛋白细胞骨架异常的重要性。我们现在建议使用我们的阿尔茨海默病和相关的tau蛋白病模型来鉴定可以改善体内神经毒性的药物。果蝇的小尺寸和短寿命允许在完整动物中筛选相对大量的化合物。我们将测试2,000种化合物（Spectrum Collection）在我们的模型中降低tau毒性的能力。我们将测试的化合物中约有一半是美国农业部批准的药物。许多其他化合物是具有预先批准的临床历史的天然产物。我们将测试的许多药物已被证明能够到达大脑。我们预期化合物的良好表征的性质将促进这些治疗化合物在脊椎动物模型中的测试和最终在临床中的应用。 公共卫生相关性：阿尔茨海默病是一种破坏性疾病，可导致严重残疾和受影响个体的早期死亡。我们将使用一种快速、廉价的体内模型系统来鉴定减少这种疾病中神经元死亡和功能障碍的化合物。我们系统的结果将提供重要的候选疗法，也可能帮助我们了解异常神经元如何在阿尔茨海默病中功能失调和死亡。

DESCRIPTION (provided by applicant): No highly effective treatment is currently available for Alzheimer's disease. To develop a suitable in vivo model for drug screening, and to investigate the basic pathogenesis of Alzheimer's disease and related disorders, we have created models of the disorder based on expression of human tau and Abeta in the fruit fly Drosophila. Our models recapitulate key features of the human disorders. Specifically, when we express human tau in Drosophila we observe shortened lifespan, behavioral abnormalities and accumulation of abnormally phosphorylated tau protein. Unbiased forward genetic screens have revealed conserved basic pathological mechanisms, including the importance of abnormal phosphorylation of tau, oxidative stress, reactivation of cell cycle in postmitotic neurons, and abnormalities of the actin cytoskeleton. We now propose using our model of Alzheimer's disease and related tauopathies to identify drugs that can ameliorate neurotoxicity in vivo. The small size and short lifespan of fruit flies allows screening of a relatively large number of compounds in intact animals. We will test the ability of 2,000 compounds (Spectrum Collection) to reduce toxicity of tau in our model. Approximately one half of the compounds we will test are USDA approved drugs. Many of the other compounds are natural products with pre-approval clinical history. Many of the drugs we will test have proven ability to reach the brain. We anticipate that the well- characterized nature of the compounds will facilitate translation of these therapeutic compounds to testing in vertebrate animal models and to eventual use in the clinic. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is a devastating disorder that causes severe disability and early death in affected individuals. We will use a fast, cheap in vivo model system to identify compounds that reduce neuronal death and dysfunction in this disease. Results from our system will provide important candidate therapeutics and may also help us understand how abnormal neurons become dysfunctional and die in Alzheimer's disease.