A novel non-transgenic fly model for tauopathies

总结 全世界有超过5500万人患有痴呆症，预计到2020年这一数字将达到7800万。 2030年，根据世界卫生组织的预测。痴呆症的主要原因是老年痴呆症 淀粉样蛋白B（Ab）斑块的存在是AD的显著分子特征， 脑内磷酸化tau蛋白。过度磷酸化tau蛋白的聚集体，如神经元缠结（NFT），见于 AD和约20种其他神经退行性疾病统称为tau蛋白病。值得注意的是 除AD外，tau蛋白病没有显著的Ab积累，表明tau蛋白在AD中的关键因果作用。 神经变性这一观点得到了许多基于小鼠模型的研究的支持。但 tau发病机理的确切性质仍然难以捉摸，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 利用果蝇Drosophila melanogaster提供的先进遗传工具，我们在cibo（ 食物）阿尔茨海默病和tau蛋白病的模型。这个模型让我们有能力诱导疾病， 成年苍蝇，并精确定义生物体暴露于的p-tau/tau的形式，两者都不是 可能使用转基因苍蝇模型。通过给成年果蝇喂食过度磷酸化的tau蛋白， 概括了果蝇AD的关键神经学特征，包括迟发性和年龄依赖性 神经变性、血脑屏障崩解和脑的不同区域中的明显病理。 这些病理特征在治疗后不到四周内变得明显，因此提供了一种治疗方法。 与其他动物模型相比，这是一个显著的优势，需要数月才能形成神经病理学。 我们研究的首要目标是使用这种新的苍蝇模型来帮助开发有效的方法， AD治疗和预防。为此，我们将使用这个探索性的R21项目来表征疾病状态 为进一步深入研究肠-脑的相互作用机制奠定了基础 神经退行性疾病的信号传导和药物发现项目。我们将使用各种方法， 了解过度磷酸化tau蛋白引起的病理学的分子基础，并检查相互作用 p-tau与已知和疑似AD贡献者如Ab、载脂蛋白E（APOE）和α-突触核蛋白之间的关系。

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.