Role of transposon dysregulation in Alzheimer and aging brains revealed by single-cell genomic and transcriptomic analysis

项目摘要 人类的衰老与许多脑部疾病有关，包括肿瘤、与年龄相关的神经变性， 和阿尔茨海默病（AD）。在许多组织中，衰老过程导致转座基因的去抑制， 导致炎症和细胞衰老的元素（TE）。最近的几项研究表明， 与健康对照相比，TE的多个亚家族在死后AD脑中以更高的水平表达， AD病理学特征的错误折叠Tau蛋白积累的直接结果。许多 AD的标志，包括神经炎症、异染色质重塑、基因组不稳定性和 最近涉及的T细胞浸润，可以由TE的激活触发。然而，由于独特的 脑中不同细胞类型的表观基因组景观结合TE动员对 细胞分裂和其他因素，TE激活的动力学和结果可能是细胞类型特异性的。 本研究旨在描述衰老和AD期间脑中TE的激活，并确定 在多种细胞类型的单个细胞水平上激活的TE的功能后果， 开发新的计算工具来回答这些问题。第一个目标是建立 在正常衰老过程中与TE相关的基因组和表观基因组变化。这一分析将有助于双方确定 TE是否参与正常的脑老化过程和与年龄相关的神经元衰退，并建立 健康对照组与AD组比较。第二个目标将执行类似的分析，这次重点是 AD和包括分离具有和不具有致病性Tau积累的神经元。最终目标将 在单细胞水平上测量前两个目标中分析的所有样品的转录组。这 测序将允许测量与先天性和适应性免疫反应相关的基因表达 以及鉴定能够触发这些反应的TE衍生序列。实验工具 和测序技术现在已经存在来研究这些问题，这项研究旨在确定 TE激活如何影响正常的大脑老化和AD。了解TE之间的关系， 神经炎症和AD病理学可能为新的治疗和治愈打开大门。

Project summary Aging in humans is associated with a host of brain diseases, including tumors, age related neurodegeneration, and Alzheimer’s Disease (AD). In many tissues, the aging process leads to a derepression of transposable elements (TEs) that lead to inflammation and cell senescence. Several recent studies have demonstrated that multiple subfamilies of TEs are expressed at higher levels in postmortem AD brain than healthy controls as a direct result of the accumulation of mis-folded Tau proteins characteristic of AD pathology. Many of the hallmarks of AD, including neuroinflammation, heterochromatin remodeling, genomic instability, and the recently implicated T-cell infiltration, can be triggered by the activation of TEs. However, because of the unique epigenomic landscape of different cell types in the brain combined with the dependence of TE mobilization on cell division and other factors, the dynamics and consequences of TE activation are likely cell-type-specific. This study aims to characterize the activation of TEs in the brain during aging and AD and identify the functional consequences of activated TEs at the level of individual cells across multiple cell types and to develop the novel computational tools necessary to answer these questions. The first aim will establish the genomic and epigenomic changes related to TEs during normal aging. This analysis will help both to determine whether TEs are involved in the normal brain aging process and age-related neuronal decline, and to establish the healthy controls for comparison with AD. The second aim will perform similar analysis, this time focusing on AD and including the separation of neurons with and without accumulation of pathogenic Tau. The final aim will measure the transcriptome at the single-cell level for all the samples profiled in the first two aims. This sequencing will allow both the measuring gene expression related to innate and adaptive immune responses and the identification of TE derived sequences capable of triggering those responses. The experimental tools and sequencing technologies now exist to examine these questions, and this study is designed to determine how TE activation impacts normal brain aging and AD. Understanding the relationship between TEs, neuroinflammation, and AD pathology may open the door for new treatments and cures.