Targeting conserved diet-responsive transcriptional networks in neurons to slow neurodegeneration in Alzheimer's disease

针对神经元中保守的饮食反应转录网络以减缓阿尔茨海默病的神经退行性变

• 批准号: 10222430
• 负责人: Pankaj Kapahi
• 金额: $ 53.35万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222430
• 关键词: Address; Affect; Age; Age of Onset; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Amyloid beta-Protein; Biological Process; Biology of Aging; Brain; Cell Cycle; ChIP-seq; Chronic; Complex; DNA Damage; Data; Defect; Dementia; Diet; Disease; Elderly; Epigenetic Process; Etiology; Gene Expression; Generations; Genes; Genetic; Genetic Models; Genetic Transcription; Glycogen; Goals; Grain; Head; Heterochromatin; Human; Intervention; Life Style; Link; Longevity; Mammals; Mediating; Metabolic dysfunction; Metabolism; Microtubule Stabilization; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nutrient; Outcome; Output; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Process; Promoter Regions; Proteome; Proteomics; Regulator Genes; Research; Role; Signal Pathway; Tauopathies; Testing; Time; Work; age related; base; dietary restriction; experimental study; extracellular; fly; functional decline; gene environment interaction; genetic manipulation; genetic risk factor; glycogen metabolism; human data; human old age (65+); improved; neuropathology; neurotoxicity; normal aging; novel; progressive neurodegeneration; protein aggregation; tau Proteins; tau mutation; therapeutic target; transcription factor

PROJECT SUMMARY/ ABSTRACT Alzheimer’s disease (AD) is a chronic neurodegenerative disorder and the most common cause of dementia amongst subjects over the age of 65. Despite identifying some of the genetic risk factors for AD, therapeutics to treat AD have been unsuccessful. A potential reason for this is that aging, the most significant risk factor for AD, has not been considered. Dietary restriction (DR) is one of the most robust interventions to slow aging and the onset of age-related diseases, including AD. However, the underlying mechanisms by which DR protects against AD are unknown. We propose to use D. melanogaster to investigate the conserved links between diet and AD for the following reasons: 1) their excellent track record for elucidating the biology of aging, neurodegenration and DR, 2) their amenability to genetic manipulation, 3) the availability of established genetic models for understanding aging and AD pathology, 4) their fast generation time and short lifespan, and 5) they share many biological processes and signaling pathways with mammals. The overall goals of this proposal are to understand the mechanisms by which DR influences AD pathology and neurodegeneration. We have observed that DR significantly improves survival and reduces the functional decline in tauopathy models of AD in flies. Importantly, our proteomic analysis suggests that mutant Tau affects the proteome of flies in a fashion that is similar to the effect of a high-nutrient diet. A comparison of our proteomic analysis from a fly tauopathy model with proteomic data from human AD brains identified 47 common genes. We also demonstrate that modulating two of the transcriptional regulators and their downstream genes modulate neurodegeneration in Tau mutant flies. Based on our preliminary data, our central hypothesis is that nutrient-dependent transcriptional networks in the brain influence neurodegeneration in pathogenic tau and AD models. We will test our hypothesis by pursuing the following specific aims. In Aim 1, we characterize the transcriptional targets altered in both fly tauopathy model and human AD for changes in neurodegeneration and lifespan in Tau and Aβ fly models of AD. In Aim 2, we characterize candidate transcriptional regulators for changes in neurodegeneration and lifespan in fly models of AD. In Aim 3, we identify the mechanisms by which nutrient-responsive transcriptional networks inhibit neurodegeneration. We focus on diet's impact on metabolism, oxidative stress, heterochromatin loss, and abortive neuronal cell-cycle activation, given that these processes are known to affect AD and aging. This research is significant, as we expect it to reveal common genetic mechanisms across species, novel targets, and lifestyle changes that slow the onset and progression of AD and related tauopathy.

项目摘要/摘要 阿尔茨海默病(AD)是一种慢性神经退行性疾病，也是导致痴呆的最常见原因 在65岁以上的受试者中。尽管确定了一些阿尔茨海默病的遗传风险因素，但治疗方法 治疗阿尔茨海默病没有成功。一个潜在的原因是衰老，这是AD最重要的风险因素， 没有被考虑过。限制饮食(DR)是延缓衰老最有力的干预措施之一， 年龄相关疾病的发病，包括阿尔茨海默病。然而，DR预防疾病的潜在机制 都是不为人知的。我们建议使用黑腹葡萄球菌来研究饮食和AD之间的保守联系。 原因如下：1)他们在阐明衰老、神经退变的生物学方面的出色记录 和DR，2)它们对遗传操作的适应性，3)已建立的遗传模型的可用性 了解衰老和阿尔茨海默病的病理，4)它们的生成时间快，寿命短，5)它们有许多共同点 哺乳动物的生物学过程和信号通路。这项建议的总体目标是理解 DR影响AD病理和神经退行性变的机制。我们观察到， 显著提高果蝇AD动物模型的存活率并减少其功能衰退。重要的是 我们的蛋白质组学分析表明，突变的Tau影响果蝇蛋白质组的方式与 高营养饮食的效果。我们对苍蝇对症模型的蛋白质组学分析与蛋白质组学分析的比较 来自人类阿尔茨海默病大脑的数据确定了47个共同基因。我们还演示了调制其中的两个 转录调节因子及其下游基因调控Tau突变果蝇的神经退行性变。 根据我们的初步数据，我们的中心假设是营养依赖的转录网络在 脑对病理性tau和AD模型神经退行性变的影响。我们将通过以下方式验证我们的假设： 以下是具体目标。在目标1中，我们描述了在两种果蝇变态反应中改变的转录靶标。 Tau和Aβ果蝇模型对AD模型和人类AD神经退行性变和寿命的影响在目标2中， 我们对果蝇模型中神经退行性变和寿命变化的候选转录调控因子进行了表征 公元一代的。在目标3中，我们确定了营养反应转录网络抑制的机制 神经退行性变。我们关注饮食对新陈代谢、氧化应激、异染色质丢失的影响，以及 流产的神经细胞周期激活，因为这些过程已知会影响AD和衰老。这 研究意义重大，因为我们希望它揭示跨物种的共同遗传机制，新的靶点， 生活方式的改变减缓了AD和相关的肌张力障碍的发生和发展。