Uncovering targets that block pathological interactions between Abeta and tau

发现阻断 Abeta 和 tau 之间病理性相互作用的靶点

• 批准号: 9373909
• 负责人: Diego E Rincon-Limas
• 金额: $ 22.88万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9373909
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Behavioral; Biological Preservation; Brain; Candidate Disease Gene; Catalogs; Complex; Data; Dementia; Development; Disease; Drosophila genus; Elderly; Experimental Models; Eye; Genes; Genetic; Genetic Screening; Goals; Histologic; Homologous Gene; Human; Impaired cognition; Intervention; Knowledge; Lesion; Libraries; Light; Mediating; Memory Loss; Microscope; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Phenotype; Play; Proteins; Public Health; RNA Interference; RNA interference screen; Research; Risk Factors; Role; Screening Result; Senile Plaques; System; Therapeutic; Time; Toxic effect; Validation; Virulence Factors; Visual; Work; abeta accumulation; abeta deposition; candidate identification; effective therapy; experimental study; extracellular; fly; neuron development; neuropathology; neurotoxicity; next generation; novel; prevent; screening; tau Proteins; tau aggregation; tau interaction; therapeutic target

ABSTRACT Alzheimer's disease (AD) is an incurable neurodegenerative disorder that causes progressive memory loss and cognitive impairment, leaving patients totally incapacitated. The two landmark lesions in AD are extracellular amyloid plaques mainly formed by the amyloid beta-42 (Abeta) peptide and intracellular neurofibrillary tangles containing aggregates of abnormal tau protein. Abeta and tau were thought of as independent culprits for a long time, but in light of recent studies, it is clear that they are intimately related and have synergistic activities. Unfortunately, very little is known about how (and which) Abeta and tau interactions trigger AD pathogenesis, which significantly impedes the development of effective therapies. To address this, we have created a new fly model of AD that genetically produces both human Abeta and wild-type tau. Our preliminary data show that these “humanized” flies display extracellular deposition of Abeta, intracellular aggregation of pathological tau, and robust neurodegeneration. The robust pathology of these flies provides an ideal platform to conduct a large-scale identification of genes that can suppress Abeta+tau neurotoxicity. Therefore, we will cross Abeta+tau flies with a next-generation library of 6,484 RNAi Drosophila strains to specifically silence human homologue genes. We will first perform a primary screen in the fly eye, which provides a fast visual result of the effect of silencing every gene (Aim 1). Then, we will validate the most potent suppressors for behavioral functions, preservation of brain neurons, and development of pathological markers (Aim 2). We anticipate that this experimental approach will uncover critical/novel targets for intervention not available to classical experimental models. Thus, the first large-scale attempt at discovering Abeta+tau suppressors will not only provide information about disease mechanisms but also identify relevant therapeutic targets to approach this overwhelming disorder. Of note, this project fits perfectly with the Strategy 1B of the National Plan to Address Alzheimer's Disease, which aims at expanding research on the molecular mechanisms and networks to enable the identification and selection of therapeutic targets.

摘要 阿尔茨海默氏病（AD）是一种无法治愈的神经退行性疾病，导致进行性记忆丧失 和认知障碍，使患者完全丧失能力。AD的两个标志性病变是 主要由淀粉样蛋白β-42（Abeta）肽形成的细胞外淀粉样蛋白斑和细胞内淀粉样蛋白斑。 含有异常tau蛋白聚集体的神经元缠结。Abeta和Tau被认为是 很长一段时间以来，他们都是独立的罪魁祸首，但根据最近的研究，很明显，他们是密切相关的， 具有协同作用。不幸的是，关于Abeta和tau如何（以及哪些）相互作用， 触发AD发病机制，这显著阻碍了有效治疗的发展。为了解决这个问题， 我们已经创建了一种新的AD果蝇模型，其在遗传上产生人Abeta和野生型tau。我们 初步数据显示，这些“人源化”果蝇显示出Abeta的细胞外沉积， 病理性tau蛋白的聚集和强烈的神经变性。这些苍蝇的强大病理学提供了一个 这是进行大规模鉴定可抑制Abeta+tau神经毒性的基因的理想平台。 因此，我们将Abeta+tau果蝇与下一代6，484个RNAi果蝇品系的文库杂交， 特异性沉默人类同源基因。我们将首先在蝇眼中执行主屏幕， 提供了沉默每个基因的效果的快速可视化结果（目的1）。然后，我们将验证最有效的 行为功能抑制剂、脑神经元保护和病理标志物的发展 (Aim 2）。我们预计，这种实验方法将发现关键/新的干预目标， 经典的实验模型。因此，首次大规模尝试发现Abeta+tau 抑制因子不仅提供有关疾病机制的信息，而且还确定相关的治疗方法。 目标是接近这种压倒性的疾病。值得注意的是，该项目完全符合战略1B， 国家计划，以解决阿尔茨海默病，其目的是扩大研究的分子 机制和网络，使识别和选择的治疗目标。