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

项目总结 人类的衰老与许多脑部疾病有关，包括肿瘤、与年龄相关的神经退行性变、 和阿尔茨海默病(AD)。在许多组织中，衰老过程导致转座子的去抑制 导致炎症和细胞衰老的元素(TE)。最近的几项研究表明， 多个TES亚家族在死后AD脑中的表达水平高于健康对照组 直接结果是错误折叠的Tau蛋白积累，这是AD病理的特征。许多人 阿尔茨海默病的特征包括神经炎症、异染色质重构、基因组不稳定和 最近发现T细胞的浸润，可由TES的激活触发。然而，由于独一无二的 脑内不同细胞类型的表观基因组图谱与TE动员的相关性 除了细胞分裂和其他因素外，TE激活的动力学和后果可能是细胞类型特有的。 本研究旨在研究衰老和阿尔茨海默病患者脑组织中TES的激活情况，并确定脑组织中TES的活性。 在跨多种细胞类型的单个细胞水平上激活TES的功能后果 开发回答这些问题所需的新型计算工具。第一个目标是建立 在正常老化过程中与TES相关的基因组和表观基因组变化。这一分析将有助于确定 TES是否参与正常的脑老化过程和衰老相关的神经元衰退，并建立 与AD作对照的健康对照。第二个目标将执行类似的分析，这一次重点是 AD和包括分离有和没有病理性Tau积聚的神经元。最终目标将是 在单细胞水平上测量前两个目标中所描述的所有样本的转录组。这 测序将允许测量与先天和获得性免疫反应相关的基因表达 以及识别能够触发这些响应的TE派生序列。实验工具 现在有测序技术来检查这些问题，这项研究旨在确定 TE的激活如何影响正常的大脑老化和AD。理解TES之间的关系， 神经炎症和AD病理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.