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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：
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.

阿尔茨海默病驱动因素与衰老之间复杂的相互作用