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.

项目概要/摘要 阿尔茨海默病 (AD) 是一种慢性神经退行性疾病，也是痴呆症的最常见原因 65 岁以上的受试者中。尽管已经确定了 AD 的一些遗传风险因素，但治疗方法 治疗 AD 不成功的一个潜在原因是衰老，这是 AD 最重要的危险因素。 饮食限制（DR）是延缓衰老的最有力的干预措施之一。 与年龄相关的疾病（包括 AD）的发病然而，DR 预防的潜在机制。 AD 未知。我们建议使用黑腹果蝇来研究饮食与 AD 之间的保守联系。 原因如下：1）他们在阐明衰老、神经退行性疾病生物学方面有着出色的记录 和 DR，2）他们对基因操作的适应性，3）已建立的遗传模型的可用性 了解衰老和 AD 病理学，4）它们的快速生成时间和短寿命，以及 5）它们有许多共同点 该提案的总体目标是了解哺乳动物的生物过程和信号传导途径。 DR 影响 AD 病理学和神经退行性变的机制 我们已经观察到 DR。 显着提高果蝇 AD tau 蛋白病模型的存活率并减少功能衰退。 我们的蛋白质组分析表明，突变型 Tau 以类似于果蝇蛋白质组的方式影响果蝇蛋白质组。 高营养饮食的影响我们的果蝇tau蛋白病模型的蛋白质组学分析与蛋白质组学的比较。 来自人类 AD 大脑的数据确定了 47 个常见基因，我们还证明了调节其中两个基因。 转录调节因子及其下游基因调节 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性转录网络 大脑影响致病性 tau 蛋白和 AD 模型中的神经变性，我们将通过追求来检验我们的假设。 在目标 1 中，我们描述了两种果蝇 tau 蛋白病中改变的转录靶点。 模型和人类 AD 中 Tau 和 Aβ 果蝇模型的神经变性和寿命变化 在目标 2 中， 我们在果蝇模型中描述了神经退行性变和寿命变化的候选转录调节因子 在目标 3 中，我们确定了营养响应转录网络抑制的机制。 我们关注饮食对新陈代谢、氧化应激、异染色质损失和神经退行性变的影响。 神经细胞周期激活失败，因为已知这些过程会影响 AD 和衰老。 研究意义重大，因为我们期望它能够揭示跨物种的共同遗传机制、新目标、 生活方式的改变可减缓 AD 和相关 tau 病的发病和进展。