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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：
9708308
负责人：
KENNETH Stephen KOSIK
金额：
$ 259.11万
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：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9708308
关键词：
Acetylation Affect Age Aging Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease pathology 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 complex data 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 single-cell RNA sequencing synaptic function synuclein tau Proteins tomography

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.

阿尔茨海默病驱动因素与衰老之间复杂的相互作用项目摘要/摘要（30 行文本）阿尔茨海默病的最大风险是年龄。这种与年龄极其紧密的相关性没有解释。然而，对阿尔茨海默氏症的了解大多来自早期发病病例。我们将利用哥伦比亚脑库中存储的 100 例早发 AD 病例，全部相同的 PSEN1[E280A] 突变，以确定由于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。一些该银行的哥伦比亚人进行了淀粉样蛋白和 tau PET 研究。散发性疾病时在老年人中，与衰老相关的大脑变化很频繁，并且在缺乏他们的情况下明确的界限，仅针对该疾病的显性遗传形式的治疗可能是无效。可能区分和促进老年人 AD 的因素包括炎症、脑血管系统受损、小胶质细胞过度增生、细胞老化（例如细胞分裂）核膜，因此 TDP-43 从细胞核中逃逸，可能突触核蛋白的贡献。我们将通过以下方式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神经病理学方法。比较将利用来自几个脑库的零星 AD 尸检。这些研究包括最先进的单细胞 RNAseq 和炎症标记物的高级评估。蜂窝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，这些神经元含有 PSEN1[E280A] 突变，旨在发现受 PSEN1[E280A] 突变影响的下游途径突变。与小胶质细胞共培养，以捕获小胶质细胞的自主和非自主效应突变将被确定。为了实现这些目标，我们组建了一支具有长期经验的多机构国际团队合作历史。洛佩拉博士是第一个认识这些家庭并管理该家庭的人阿尔茨海默病预防试验是美国国立卫生研究院支持的项目哥伦比亚团队的负责人。支持在神经病理学方面，我们聘请了 Eric Huang 博士的专业知识。科西克几乎有与 Lopera 合作 30 年，熟悉哥伦比亚的研究开展情况最近与 Eric Huang 一起参观了哥伦比亚脑库。科西克紧密相连通过与 Bruce 一起担任 Tau 联盟联合董事，与 UCSF 建立了机构关系磨坊主。 Kosik 曾与 Ellisman 合作发表文章，并担任国家实验室审查委员会成员加州大学圣地亚哥分校显微镜和成像研究中心。因此，该项目包括强大、经验丰富且高度整合的团队能够执行复杂的项目处理不可避免出现的任何障碍。