Cell-specific genomic features of Alzheimer's disease progression

年龄是阿尔茨海默病(AD)的主要危险因素。专注于联系的人体研究 在衰老的转录组学和表观基因组学之间以及它们与阿尔茨海默病的关系之间有很大的希望 解开AD的分子基础，提供新的治疗靶点。转录和表观基因组学 到目前为止，已报道的研究受到一些方法学问题的阻碍，特别是使用 异质细胞混合物。使用来自1,263名受试者的纯化单核细胞转录转录图谱 动脉粥样硬化(MESA)的多种族研究，我们报告了一个共表达的氧化转录网络 随着年龄增长而下降的磷酸化(OXPHOS)基因。我们下面的转录分析证明了 这个由21个基因组成的OXPHOS网络(FDRs&lt；0.05)与认知功能呈正相关。这些 人类数据，结合我们的非人类灵长类数据，将单核细胞和 额叶皮质组织和转基因小鼠的最新数据显示线粒体功能障碍在 AD，提示单核细胞转录图谱可能反映了大脑生物能量功能障碍与年龄有关 广告。鉴于在小鼠身上新出现的证据表明单核细胞可以渗透到大脑并接管免疫 监测，我们的数据也表明单核细胞功能改变可能影响AD。不管怎样，我们的十字架- 人类部分数据不能确定OXPHOS的基因组改变是原因还是结果 广告。这项拟议的研究的目标是确定细胞特异性基因网络的影响，特别是衰老- 相关网络，如OXPHOS，通过对基因组的综合分析促进AD的发展， 以社区为基础的纵向研究中的表观基因组和转录组数据。深表型台地 队列，具有在考试5(2010-11)中收集的独特的表观基因组、转录组和认知数据， 提供了一个理想的学习群体。我们建议重复表观基因组、转录和认知 在考试6(2016-17)中进行评估，并执行统一数据集的认知电池，以启用 在考试6和三年后确定轻度认知障碍(MCI)和阿尔茨海默病 MESA队列(N=1,200)的子集，以实现以下特定目标：1)确定是否老化- 转录/表观基因组图谱的相关变化预测6年后认知能力下降；2) 确定转录/表观基因组谱中与衰老相关的变化是否预示AD的发展 超过三年的随访；以及3)确定线粒体活动和含量的差异， 从OXPHOS的改变中可以预测到，这与AD的发生有关。这个巨大的，有前景的 多组学研究将采取一种新的方法，专注于人类与衰老相关的基因网络 同质细胞为AD的发展确定新的生物标志物，这是理解AD的关键一步 并为早期干预提供线索。

Age is the primary risk factor for Alzheimer's disease (AD). Human studies that focus on the connections between transcriptomics and epigenomics of aging and their relationship to AD hold great promise for unraveling the molecular basis of AD and providing novel therapeutic targets. Transcriptomic and epigenomic studies reported to date have been hampered by a number of methodologic issues, especially the use of heterogeneous cell mixtures. Using transcriptomic profiles in purified monocytes from 1,263 participants of the Multi-Ethnic Study of Atherosclerosis (MESA), we reported a transcriptional network of co-expressed oxidative phosphorylation (OXPHOS) genes that decline with age. Our following transcriptomic analysis demonstrated that this OXPHOS network of 21 genes (FDRs<0.05) were positively associated with cognitive function. These human data, combined with our non-human primate data correlating mitochondrial function of monocytes and frontal cortex tissue and recent data in transgenic mice showing a causal role of mitochondrial dysfunction in AD, suggest that monocyte transcriptional profiles may reflect brain bioenergetic dysfunctions linking age to AD. Given emerging evidence in mice that monocytes can infiltrate the brain and take over immune surveillance, our data also suggest that altered monocyte function may affect AD. Nevertheless, our cross- sectional human data cannot determine whether genomic alteration of OXPHOS is a cause or consequence of AD. The goal of the proposed study is to determine the impact of cell specific gene networks, especially aging- related networks such as OXPHOS, on the development of AD through an integrated analysis of genomic, epigenomic and transcriptomic data in a longitudinal community-based study. The deeply phenotyped MESA cohort, with unique existing epigenomic, transcriptomic and cognitive data collected at Exam 5 (2010-11), offers an ideal study population. We propose to repeat the epigenomic, transcriptomic and cognitive assessment at Exam 6 (2016-17) and perform the cognitive battery of the Uniform Data Set to enable ascertainment of mild cognitive impairment (MCI) and Alzheimer's dementia at Exam 6 and three years later in a subset of MESA cohort (N=1,200) to achieve the following specific aims: 1) To determine whether aging- related changes in transcriptomic/epigenomic profiles predict cognitive decline over a 6-year follow-up; 2) To determine whether aging-related changes in transcriptomic/epigenomic profiles predict development of AD over a three-year follow-up; and 3) To determine whether differences in mitochondrial activity and content, which would be predicted from the OXPHOS alterations, relate to development of AD. This large, prospective multi-omic study will take a novel approach of focusing on aging-related gene networks in human homogeneous cells to identify new biomarkers for AD development, a crucial step forward in understanding cell-specific mechanisms and providing clues to early intervention.