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

摘要 阿尔茨海默病（AD）是最常见的痴呆和神经变性形式，影响超过5 美国人目前没有有效的治疗方法。几种孟德尔突变和风险变体 被识别。我们和其他人已经表明，AD与脑细胞比例的变化有关， 转录组的变化，其中一些也是细胞特异性的。此外，最新的基因研究表明， 导致疾病的细胞特异性致病事件。APP、PSEN1和PSEN2中的致病性变体影响 APP加工导致Aβ聚集体和神经元死亡。TREM2和MS4A中的遗传变体修饰 AD风险通过影响小胶质细胞的活动。充分理解和描述转座因子的作用 (TE)在AD发病机制中，需要新的和多学科的方法。在这里我们将联合收割机 在人脑组织中，直接转化的神经元和iPSC衍生的小胶质细胞（iMGL）， 鉴定AD中涉及的细胞特异性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资源和来自个体的成纤维细胞， APP、PSEN 1、PSEN 2中的突变以及TREM 2、MS 4A或APOE中的风险变体。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，以靶向和表征 TE导致疾病的机制。

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.