The complex interaction between Alzheimer drivers and aging

阿尔茨海默病驱动因素与衰老之间复杂的相互作用

基本信息

批准号：
9892174
负责人：
KENNETH Stephen KOSIK
金额：
$ 73.24万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9892174
关键词：
AD pathology Acetylation Affect Age Aging Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Antibodies Antigens Astrocytes Astrocytosis Attention Autopsy Brain Cell Aging Cell Differentiation process Cell Nucleus Cell model Cells Cerebrovascular system Characteristics Coculture Techniques Collaborations Collection Colombia Colombian Complex Consequentialism Cytokine Gene Cytoplasm Data Data Set Defect Disease Dominant Genetic Conditions Elderly Expression Profiling Extravasation Fibroblasts Foundations Gene Expression Gene Mutation Glial Fibrillary Acidic Protein Head Human Immunohistochemistry Individual Inflammation Interleukin-1 alpha Interleukin-1 beta Interleukin-6 International Link Literature Maryland Mediating Mendelian disorder Methods Microglia Modification Mutation Neurons New York Nuclear Nuclear Envelope Onset of illness PECAM1 gene Pathology Pathway interactions Patients Pericytes Phenotype Phosphorylation Population Positron-Emission Tomography Preparation Presenile Alzheimer Dementia Prevention trial Publishing Recording of previous events Research Resource Development Role Sampling Smooth Muscle Myocytes Statistical Data Interpretation Synapses System TNF gene TREM2 gene Techniques Testing Text Tissue Banks Tissues Travel Ubiquitination United States National Institutes of Health Universities Variant Vascular Smooth Muscle Visit Work age related alpha synuclein base brain tissue cell type early onset experience family management genome wide association study immunocytochemistry induced pluripotent stem cell inflammatory marker loss of function microscopic imaging mind control neuroinflammation neuropathology novel presenilin-1 protein TDP-43 response single cell analysis synaptic function synuclein tau Proteins tomography transcriptome sequencing

项目摘要

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.

阿尔茨海默氏症驱动程序与老化之间的复杂相互作用项目摘要/摘要（文本30行）阿尔茨海默氏病的最大风险是年龄。与年龄的这种非常紧密的相关性没有解释。但是，大多数对阿尔茨海默氏症的了解都来自早发病例。我们将利用哥伦比亚脑库中存储的100例早期发作广告，相同的PSEN1 [E280A]突变，以确定由于A而观察到的全部病理范围单基因缺陷并将这些数据与零星的老年发作疾病进行比较。一些银行中的哥伦比亚个人进行了淀粉样蛋白和TAU宠物研究。在零星疾病中在古老的情况下，大脑变化与衰老有关明确的描述，仅针对疾病的主要遗传形式的治疗可能是无效。可能会区分和促进广告的因素，包括注射，脑脉管系统损害，多胶质细胞增多，细胞衰老，例如分解 TDP-43从核和可能的突触核素的贡献。 We will explore interactions of these factors with aging through 描述性神经病理学和实验神经病理学方法。比较将使用来自几家脑库的零星广告后验尸。这些研究包括艺术状态单细胞RNASEQ和炎症标记的高级评估。蜂窝模型将是使用人类诱导的多能干细胞衍生的神经元进行探索，该神经元具有 PSEN1 [E280A]突变，旨在发现受psen1的下游途径突变。与小胶质细胞共培养以捕获自主和非自主效应将确定突变。为了实现目标，我们组装了一个多机构的国际团队协作历史。 Lopera博士，他首先认识到家庭并管理阿尔茨海默氏症预防试验，负责NIH支持项目的哥伦比亚团队。支持我们的神经病理学努力我们招募了Eric Huang博士的专业知识。 Kosik靠近与Lopera的30年合作，熟悉哥伦比亚和最近旅行与埃里克·黄（Eric Huang）一起访问哥伦比亚大脑银行。 Kosik紧密连接通过与布鲁斯一起担任TAU财团的联合导演的角色与UCSF在制度上与磨坊主。 Kosik已与Ellisman一起出版，并在国家审查委员会任职 UCSD的显微镜和成像研究中心。该项目由强大，经验丰富且高度集成的团队能够进行一个复杂的项目，并且处理不可避免地会出现的任何障碍。