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

项目总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种慢性神经退行性疾病，是痴呆的最常见病因 在65岁以上的受试者中。尽管确定了AD的一些遗传风险因素， 治疗AD一直不成功。一个潜在的原因是衰老，AD最重要的风险因素， 没有被考虑过。饮食限制（DR）是减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。但是，灾难恢复保护的底层机制 AD未知。我们建议使用D。研究饮食与AD之间的保守联系 原因如下：1）他们在阐明衰老生物学、神经退行性变 和DR，2）它们对遗传操作的顺从性，3）已建立的遗传模型的可用性， 了解衰老和AD病理学，4）他们的快速世代时间和短寿命，以及5）他们分享许多 与哺乳动物的生物过程和信号通路。本提案的总体目标是了解 DR影响AD病理和神经退行性变的机制。我们注意到，DR 显著提高存活率并减少果蝇中AD的tau蛋白病模型的功能下降。重要的是， 我们的蛋白质组学分析表明，突变的Tau蛋白以类似于 高营养饮食的影响。我们对果蝇tau蛋白病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AD大脑的数据确定了47个共同基因。我们还证明，调制两个 转录调节因子及其下游基因调节Tau突变果蝇的神经变性。 根据我们的初步数据，我们的中心假设是，在细胞中的营养依赖性转录网络， 脑影响致病性tau和AD模型中的神经变性。我们将通过追踪 以下具体目标。在目标1中，我们描述了在两种果蝇tau蛋白病中改变的转录靶点， AD的Tau和Aβ果蝇模型中神经变性和寿命的变化。在目标2中， 我们描述了果蝇模型中神经变性和寿命变化的候选转录调节因子， 的AD。在目标3中，我们确定了营养响应转录网络抑制 神经变性我们专注于饮食对新陈代谢、氧化应激、异染色质丢失和 失败的神经元细胞周期激活，因为这些过程已知会影响AD和衰老。这 研究意义重大，因为我们希望它能揭示跨物种的共同遗传机制，新的靶点， 以及减缓AD和相关tau蛋白病的发作和进展的生活方式改变。

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.