A novel non-transgenic fly model for tauopathies

摘要 全世界有超过5500万人患有痴呆症，预计到2010年这一数字将达到7800万 根据世界卫生组织的预测，2030年。痴呆症的主要原因是阿尔茨海默氏症 疾病(AD)，其分子特征是淀粉样蛋白b(Ab)斑块的存在，以及异常 大脑中的磷酸化tau。过度磷酸化的tau聚集成神经原纤维缠结(NFT)在 AD和大约20种其他神经退行性疾病统称为tauopathies。值得注意的是， 除AD外，tau病没有显著的抗体蓄积，这表明tau在AD中起着关键的因果作用 神经退行性变。这一观点得到了许多基于老鼠模型的研究的支持。然而， Tau的确切发病机制仍不清楚，因此阻碍了有效的药物开发。解剖 过度磷酸化tau介导的神经变性的机制细节，并利用 由果蝇提供的先进遗传工具，我们在Cibo(In)建立了一个新的 食物)阿尔茨海默氏症和肥胖症的模型。这种模型使我们能够在体内诱发疾病 并精确定义了有机体接触的p-tau/tau的形式，这两种形式都不是 使用转基因果蝇模型是可能的。通过给成年果蝇喂食过度磷酸化的tau，我们已经 概述了果蝇阿尔茨海默病的关键神经学特征，包括起病晚和年龄依赖性 神经变性，血脑屏障解体，大脑不同区域有明显的病理改变。 这些病理特征在治疗后不到四周内变得明显，因此提供了一种 与其他需要几个月才能形成神经病理的动物模型相比，具有显著的优势。 我们研究的首要目标是利用这种新颖的苍蝇模型来帮助开发有效的方法来 AD的治疗和预防。为此，我们将使用这个探索性的R21项目来描述疾病状态 为今后深入了解肠脑的全面机制研究奠定了基础 神经退行性疾病和药物发现项目中的信号。我们将使用各种方法来 了解过度磷酸化tau引起的病理的分子基础，并检查其相互作用。 P-tau与已知和可疑的AD贡献者之间的关系，如抗体、载脂蛋白E(APOE)和a-突触核蛋白。

SUMMARY Over 55 million people live with dementia worldwide, and this number is expected to reach 78 million by 2030, according to the projection by the World Health Organization. The main cause of dementia is Alzheimer’s disease (AD), whose distinguishing molecular feature is the presence of amyloid b (Ab) plaques, and abnormally phosphorylated tau in brain. Aggregates of hyperphosphorylated tau as neurofibrillary tangles (NFT) are seen in AD and about 20 other neurodegenerative disorders collectively known as tauopathies. It is noteworthy that except AD, tauopathies do not have significant Ab accumulation, suggesting a key causal role of tau in neurodegeneration. This notion has been supported by many studies based on mouse models. However, the exact nature of tau pathogenesis remains elusive, therefore hampering effective drug development. To dissect the mechanistic details of hyperphosphorylated tau-mediated neurodegeneration, and to take advantage of the advanced genetic tools offered by the fruit fly Drosophila melanogaster, we have established a novel in cibo (in food) model of Alzheimer’s disease and tauopathies. This model gives us the ability to induce the disease in adult flies, and precisely define the form of p-tau/tau that the organism is exposed to, both of which are not possible using a transgenic fly model. By feeding adult Drosophila with hyperphosphorylated tau, we have recapitulated critical neurological features of AD in flies, including the late onset and age-dependent neurodegeneration, disintegrated blood brain barrier, and conspicuous pathology in different areas of the brain. These pathological traits become evident in less than four weeks after the treatment, therefore providing a significant advantage over other animal models that take months to develop neurological pathology. The overarching goal of our research is to use this novel fly model to help develop efficacious means for AD therapy and prevention. To this end, we will use this exploratory R21 project to characterize the disease state of this model and lay the foundation for future comprehensive mechanistic studies to understand gut-brain signaling in neurodegenerative diseases, and drug discovery projects. We will use a variety of approaches to understand the molecular basis for hyperphosphorylated tau-inflicted pathology, and examine the interplay between p-tau and known and suspected AD contributors such as Ab, apolipoprotein E (APOE), and a-synuclein.