Pharmacological modulation of tau neurotoxicity in vivo

描述（由申请人提供）：阿尔茨海默病目前没有非常有效的治疗方法。为了建立一个适合药物筛选的体内模型，并研究阿尔茨海默病和相关疾病的基本发病机制，我们基于人类tau和Abeta在果蝇中的表达建立了该疾病的模型。我们的模型概括了人类疾病的主要特征。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。无偏倚的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模型和相关的牛头病变来确定可以改善体内神经毒性的药物。果蝇的体积小，寿命短，因此可以在完整的动物中筛选相对较多的化合物。我们将在我们的模型中测试2000种化合物（光谱收集）降低tau毒性的能力。我们将测试的化合物中大约有一半是美国农业部批准的药物。许多其他化合物是天然产物，具有预先批准的临床历史。我们将要测试的许多药物已经被证明能够到达大脑。我们预计，这些化合物的良好特性将有助于这些治疗性化合物在脊椎动物模型中进行测试，并最终用于临床。

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.