The complex interaction between Alzheimer drivers and aging

阿尔茨海默病司机与衰老之间的复杂相互作用 项目摘要/摘要(30行文本) 老年痴呆症的最大风险是年龄。这种与年龄的极其密切的相关性 没有任何解释。然而，人们对阿尔茨海默氏症的了解大多来自早发性病例。 我们将利用哥伦比亚脑库中存储的100例早发性AD病例，所有病例都具有 相同的PSEN1[E280A]突变以确定由于 单基因缺陷，并将这些数据与散发性老年疾病进行比较。其中一些 银行中的哥伦比亚人已经进行了淀粉样蛋白和tau PET研究。在散发性疾病中 在老年人中，与衰老有关的大脑变化是频繁的，如果没有他们的大脑 清楚地描述，仅针对疾病的显性遗传形式的治疗可能是 效果不佳。可能在老年人中区分和促进AD的因素包括炎症， 脑血管受损，小胶质细胞过度增生，细胞老化，如脑血管 核膜和TDP-43因此从细胞核逃逸的可能性 突触核蛋白的贡献。我们将通过以下途径探索这些因素与衰老的相互作用 描述性神经病理学和实验性神经病理学方法。比较将利用 几个脑库的零星AD尸检。这些研究包括最先进的 单细胞RNAseq和炎症标志物的高级评估。细胞模型将是 探索使用人类诱导的多能干细胞来源的神经元 PSEN1[E280A]突变，旨在发现受PSEN1[E280A]突变影响的下游通路 突变。与小胶质细胞共培养以捕捉自主和非自主的影响 突变将被确定。 为了实现这些目标，我们组建了一支由多个机构组成的国际团队， 合作的历史。洛佩拉博士，他首先认出了这些家庭，并管理着 阿尔茨海默病预防试验，领导哥伦比亚的团队，这是NIH支持的一个项目。支持 在神经病理学方面，我们征求了黄瑞克博士的专业意见。Kosik有一个几乎 与洛佩拉合作30年，熟悉哥伦比亚的研究工作， 最近和Eric Huang一起旅行参观了哥伦比亚的脑库。Kosik是紧密相连的 通过与布鲁斯一起担任Tau财团的联席董事，在制度上与加州大学旧金山分校合作 米勒。Kosik与Ellisman一起发表了文章，并在国家 加州大学圣迭戈分校显微镜和成像研究中心。因此，该项目由一个 强大、经验丰富、高度整合的团队，能够执行复杂的项目和 处理任何不可避免地会出现的障碍。

The complex interaction between Alzheimer drivers and aging Project Summary/Abstract (30 lines of text) The greatest risk for Alzheimer’s disease is age. This extremely tight correlation with age has no explanation. However, most of what know about Alzheimer’s comes from early onset cases. We will utilize the 100 cases of early onset AD stored in the Colombian brain bank all with the same PSEN1[E280A] mutation to determine the full range of pathology observed due to a monogenic defect and compare these data to sporadic older onset disease. Some of the Colombian individuals in the bank have had amyloid and tau PET studies. In sporadic disease among the elderly, brain changes related to aging are frequent and in the absence of their clear delineation, treatments targeted solely at dominant genetic forms of the disease may be ineffective. Factors which might distinguish and promote AD in the elderly include inflammation, compromised brain vasculature, excessive microgliosis, cellular aging such as break down of the nuclear membrane and consequently escape of TDP-43 from the nucleus and possible contributions of synuclein. We will explore interactions of these factors with aging through descriptive neuropathology and experimental neuropathology methods. Comparisons will utilize sporadic AD post-mortem from several brain banks. These studies include state of the art single cell RNAseq and advanced assessment of inflammation markers. Cellular models will be explored using human induced pluripotent stem cell-derived neurons that harbor the PSEN1[E280A] mutation and are intended to discover downstream pathways affected by the mutation. Co-cultures with microglia to capture autonomous and non-autonomous effects of the mutation will be determined. To accomplish the aims we have assembled a multi-institutional international team with a long history of collaboration. Dr. Lopera, who first recognized the families and manages the Alzheimer Prevention Trial, heads the team in Colombia, an NIH supported project. To support the neuropathology effort we have enlisted the expertise of Dr. Eric Huang. Kosik has a nearly 30 year collaboration with Lopera, is familiar with the conduct of research in Colombia and recently traveled to visit the Colombian brain bank with Eric Huang. Kosik is closely connected institutionally with UCSF through his role as co-director of the Tau Consortium along with Bruce Miller. Kosik has published with Ellisman and serves on the review board for the National Center for Microscopy and Imaging Research center at UCSD. Thus the project consists of a strong, experienced and highly integrated team capable of conducting a complex project and dealing with any of the obstacles that will inevitably arise.