Identification and Characterization of Cell-Specific Transposable Elements Implicated on Alzheimer Disease and Healthy Aging

摘要 阿尔茨海默病(AD)是痴呆症最常见的形式，影响超过5 数百万美国人目前没有得到有效的治疗。几个孟德尔式的突变和风险变异 已被确认身份。我们和其他人已经证明阿尔茨海默病与脑细胞比例的变化和 转录的变化，其中一些也是细胞特有的。此外，最新的基因研究表明， 导致疾病的特定细胞致病事件。APP、PSEN1和PSEN2致病变异影响 APP处理导致Aβ聚集和神经元死亡。TREM2和MS4A的遗传变异修改 通过影响小胶质细胞的活动来增加AD的风险。充分理解和表征转座元件的作用 (TE)AD的发病机制需要新的、多学科的研究方法。在这里，我们将结合小说 人脑组织、直接转化神经元和iPSC来源的小胶质细胞(IMGL)的基因组方法 确定AD所涉及的细胞特异性TE和下游(染色质可及性、转录)变化。我们 将利用大量独特的人脑样本和来自 APP、PSEN1、PSEN2的突变，以及TREM2、MS4A或APOE的风险变异。我们还将使用 直接转化的神经元和iMGL，以及新的基因组编辑方法来靶向和表征 TE致病的机制。

Abstract Alzheimer disease (AD) is the most common form of dementia and neurodegeneration affecting more than 5 million Americans with no current effective treatment. Several Mendelian mutations and risk variants have been identified. We and others have shown that AD is associated with changes in brain cell proportion and transcriptomic changes, some of them are also cell specific. Additionally, the latest genetic studies implicate cell-specific pathogenic events that lead to disease. Pathogenic variants in APP, PSEN1 and PSEN2 affects APP processing leading to Aβ aggregates and neuronal death. Genetic variants in TREM2 and MS4A modify AD risk by affecting microglia activity. To fully understand and characterize the role of transposable elements (TE) in AD pathogenesis there is a need to novel and multidisciplinary approaches. Here we will combine novel genomic approaches in human brain tissues, direct converted neurons and iPSC-derived microglia (iMGL) to identify cell-specific TE and downstream (chromatin accessibility, transcription) changes implicated in AD. We will leverage a large and unique resources of human brain samples and fibroblast from individuals with mutations in APP, PSEN1, PSEN2, as well as risk variants in TREM2, MS4A or APOE. We will also use the direct converted neurons and iMGL, together with new genomic editing approaches to target and characterize the mechanism by which TE contribute to disease.