Molecular consequences of protein regulation on amyloid plaque burden

项目总结/摘要 在美国有近600万阿尔茨海默病（AD）患者，目前 据预测，到2050年，将有超过1400万人受到影响。AD的病理特征是细胞外 淀粉样斑块和神经纤维缠结。然而，尽管密集的研究集中在这些特征上， 不了解认知能力下降的机制基础，也不了解斑块和缠结是如何参与的。年龄 是神经退行性变的最大风险因素，但连接正常衰老和 神经退行性疾病尚不清楚。热量限制（CR）没有营养不良延迟衰老和年龄- 相关疾病，包括神经退行性疾病。在非人灵长类动物中进行的CR长期试验 威斯康星大学麦迪逊分校（UW）的恒河猴已经证实，CR的好处转化为 灵长类动物大规模的分子分析工作，以了解这些动物的CR反应，揭示了 生长、免疫和炎症途径的一般下调和代谢途径的上调。 肝脏对短期CR的反应包括RNA加工机制的新作用，例如替代性的RNA加工机制。 剪接;外显子使用模式的变化在CR招募的代谢网络中广泛存在。 恒河猴在其平均寿命26年左右自发形成斑块， 年龄因此，来自UW老化和CR研究的库存脑标本代表了一个重要的机会， 在一个高度可翻译的模型中研究衰老背景下的AD病理学。这项研究的目的是使用深度 测序蛋白质组学以研究来自RNA加工事件的蛋白质同种型的产生， 确定它们如何与三个大脑区域的淀粉样斑块负荷相关。这些数据将被 与RNAseq和其他已经存在或正在从这些动物收集的数据相结合， 包括tau蛋白、外周胰岛素敏感性、小胶质细胞、认知、代谢和其他指标， 将RNA加工与下游AD病理学和全身代谢健康联系起来。

PROJECT SUMMARY/ABSTRACT There are almost 6 million individuals with Alzheimer's disease (AD) in the United States, and current predictions suggest over 14 million will be affected by 2050. AD is characterized pathologically by extracellular amyloid plaques and neurofibrillary tangles. However, despite intense research focus on these features we still don't understand the mechanistic basis for cognitive decline or how the plaques and tangles are involved. Age is the largest risk factor for neurodegeneration but the molecular details that connect normal aging and neurodegenerative diseases are unclear. Caloric restriction (CR) without malnutrition delays aging and age- related diseases, including neurodegenerative diseases. A long-running trial of CR in the non-human primate rhesus monkey at the University of Wisconsin-Madison (UW) has confirmed that the benefits of CR translate to primates. Large-scale molecular profiling work to understand the CR response in these animals has revealed general downregulation of growth, immune, and inflammatory pathways and upregulation of metabolic pathways. The hepatic response to short-term CR included a novel role for RNA processing mechanisms such as alternative splicing; changes to exon usage patterns were widespread across the metabolic network recruited by CR. Rhesus monkeys develop plaques spontaneously beginning around their median lifespan of 26 years of age. Banked brain specimens from the UW Aging and CR study therefore represent a significant opportunity to study AD pathology in the context of aging in a highly translatable model. The goal of this study is to use deep sequencing proteomics to investigate the production of protein isoforms from RNA processing events and determine how they correlate with amyloid plaque burden in three brain regions. These data will then be integrated with RNAseq and other data already existing or in the process of being collected from these animals, including tau, peripheral insulin sensitivity, microglia, cognition, metabolism, and other indices, ultimately connecting RNA processing to downstream AD pathology and systemic metabolic health.