QUANTITATIVE PROTEOMICS OF ALZHEIMER'S DISEASE HUMAN BRAIN

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 晚发性阿尔茨海默病（late onset Alzheimer 'sdisease，LOAD）是最常见的神经退行性疾病之一，其分子病因学尚未完全阐明。 此外，LOAD没有显示出任何明显的遗传模式，使基于遗传背景的诊断复杂化。 为了研究LOAD的分子机制以及与遗传背景的潜在联系，我们使用Affymetrix 500 K芯片进行了全基因组SNP基因分型，并使用Illumina ref-seq 8芯片对一系列193个神经病理正常人脑和177个样本进行了转录组表达分析来自LOAD大脑。 到目前为止，我们已经分析和描述了SNP多态性与正常个体大脑基因表达谱的相关性，目前正在检查LOAD系列以寻找可能参与疾病过程的控制RNA表达的DNA变体。 然而，结合蛋白质丰度测量分析这些数据非常重要，因为阿尔茨海默病的主要分子标志是蛋白质聚集，这表明蛋白质生物合成和降解失调。 蛋白质聚集体：老年斑和神经纤维缠结主要由淀粉样β蛋白组成。 然而，最近通过激光捕获显微切割获得的老年斑和神经纤维缠结的LC-MS/MS蛋白质组学分析研究表明，这些蛋白质聚集体更复杂，估计蛋白质数量分别为约25和约60。 我们建议目前的研究，以定量分析人类蛋白质组与高通量纳米LC FTICR MS在有限的子集正常和负载的大脑，研究遗传多态性，基因表达谱和蛋白质丰度谱之间的潜在联系，重点是蛋白质聚集。定量蛋白质组分析将是一个非常有价值的除了已经收集的数据基因组和转录组分析正常和负载人脑。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Although late onset Alzheimer's disease (LOAD) is one of the most common neurodegenerative disorders its molecular etiology is far from being completely understood. In addition LOAD does not show any obvious inheritance pattern, complicating the diagnostics based on genetic background. To study the molecular mechanisms of the LOAD and potential links to the genetic background we have performed whole genome SNP genotyping using the Affymetrix 500K chips and transcriptome expression analysis using the Illumina ref-seq 8 chips on a series of 193 neuropathologically normal human brains and 177 samples from LOAD brains. So far we have analyzed and described the correlation of SNP polymorphism with gene expression profiles for brains from normal individuals and currently in the process of examining the LOAD series to look for DNA variants controlling RNA expression that might be involved in disease processes. However, it is very important to analyze this data in conjunction with protein abundance measurements, as the main molecular hallmark of Alzheimer's disease is the protein aggregation, which is pointing to dis-regulation of protein biosynthesis and degradation. The protein aggregates: senile plaques and neurofibrillary tangles predominantly consist of amyloid beta protein. However the recent LC-MS/MS proteomic profiling studies of senile plaques and neurofibrillary tangles obtained by laser capture microdissection have shown that those protein aggregates are more complex with estimated number of proteins ~25 and ~60, respectively. We propose for the current study to quantitatively analyze the human proteome with high throughput nano-LC FTICR MS in a limited subset normal and LOAD brains to investigate the potential links between genetic polymorphism, gene expression profiles, and protein abundance profiles with emphasis on protein aggregation. The quantitative proteome profiling is going to be a highly valuable addition to already collected data on genome and transcriptome profiling of normal and LOAD human brains.