The complex interaction between Alzheimer drivers and aging

阿尔茨海默病驱动因素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。这种与年龄的紧密联系 没有解释。然而，大多数关于阿尔茨海默氏症的知识来自早期发病病例。 我们将利用哥伦比亚脑库中储存的100例早发性AD病例， 相同的PSEN 1 [E280 A]突变，以确定由于PSEN 1 [E280 A]突变而观察到的全部病理学。 单基因缺陷，并将这些数据与散发性老年发病疾病进行比较。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， 明确划定，治疗只针对显性遗传形式的疾病可能是 无效。可能区分和促进老年人AD的因素包括炎症， 受损的脑血管系统、过度的小胶质细胞增生、细胞老化，例如 因此TDP-43从细胞核逃逸， synuclein的贡献。我们将探讨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 几个脑库中发现的零星AD这些研究包括最新技术水平 单细胞RNAseq和炎症标志物的高级评估。细胞模型将是 使用人类诱导多能干细胞衍生的神经元进行探索， PSEN 1 [E280 A]突变，旨在发现受PSEN 1 [E280 A]突变影响的下游途径。 突变与小胶质细胞共培养，以捕获 突变将被确定。 为了实现这些目标，我们组建了一个多机构的国际团队， 合作的历史。Lopera博士是第一个认识到这些家庭并管理 阿尔茨海默病预防试验，领导哥伦比亚的团队，这是一个NIH支持的项目。支持 神经病理学的研究，我们邀请到了埃里克·黄博士的专业知识。科西克几乎 与Lopera合作30年，熟悉哥伦比亚的研究工作， 最近和埃里克·黄一起去参观了哥伦比亚的脑库。科西克与 通过他与布鲁斯一起担任Tau联盟沿着主任， 米勒。Kosik曾与Ellisman一起出版，并在国家审查委员会任职。 加州大学圣地亚哥分校显微镜和成像研究中心。因此，该项目包括一个 强大、经验丰富、高度整合的团队，能够开展复杂的项目， 解决不可避免的障碍

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.