权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Tau pathology in neurons, glia, and cell type-specific exosomes from cryopreserved AD cortex

冷冻保存的 AD 皮层神经元、神经胶质细胞和细胞类型特异性外泌体中的 Tau 病理学

基本信息

批准号：
9917554
负责人：
Tina Bilousova
金额：
$ 42.9万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2020-01-15 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917554
关键词：
Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amyloid beta-Protein Animals Astrocytes Autopsy Basic Science Brain Brain Diseases CCL2 gene CX3CR1 gene Cell Communication Cells Cryopreservation Cryopreserved Cell Cytometry Data Dendritic Spines Disease Dissociation Endothelial Cells Flow Cytometry Foundations Future Genetic Goals Health Homeostasis Hour Human ITGAM gene Immune Immunotherapy Inflammation Inflammation Mediators Inflammatory Label Literature Mediating Methods Microglia Modeling Mus Mutation Nerve Degeneration Neuroglia Neurons Oligodendroglia Paper Pathology Pathway interactions Phagocytes Population Preparation Proteins Protocols documentation Reagent Reporting Research Rodent Role Sampling Signal Transduction Supporting Cell Synapses System TNF gene TREM2 gene Tauopathies Techniques Time Tissue Sample Translations Validation Vesicle Work aged brain cell brain tissue case control cell type cytokine density exosome experimental study extracellular vesicles human study improved interest method development mind control mouse model nanoscale novel programs single-cell RNA sequencing tau Proteins tau-1 three dimensional cell culture transcription factor transcriptomics vesicular release

项目摘要

Project Summary The present project has the goal of developing flow cytometry methods to analyze glia and neurons within enzymatically dissociated cells from cryopreserved human cortex, and to simultaneously isolate cell-specific extracelleular vesicles(EVs)/exosomes from the same tissue samples. As a proof of concept initial hypothesis, we expect to observe stage-mediated tau increases in AD neurons and glia, and in EVs from the same samples. An extensive literature documents the importance of synaptic tau propagation in Alzheimer's disease and other tauopathies tau immunotherapy has shown efficacy in more than 13 studies. More recent studies demonstrate a major role for microglia and possibly astrocytes in the spread of neuronal tau pathology, but to our knowledge, no approach exists to analyze multiple brain cell types from the same human brain. Samples will come from our bank, developed over decades, of more than 350 postmortem AD and aged control cortex samples that are cryopreserved at the time of autopsy. A tauopathy mouse model that expresses human tau will also be studied. Aim 1 will optimize flow cytometry methods to identify and isolate neurons, astrocytes and microglia in dissociated cells from cryopreserved AD cortex. Aim 2 will isolate exosome/EVs from each AD cortical sample at the time of dissociation, and isolate tau-bearing EVs of neuronal, astrocyte and microglial origin. This proposal will directly address the contribution of the major brain cell types to tau progression in AD, at the same time considering the role of exosomes from each cell type. The proposed protocols are highly novel and will maximize the use of postmortem samples and our flow cytometry expertise.

项目概要本项目的目标是开发流式细胞术方法来分析神经胶质细胞和神经元从冷冻保存的人类皮质中酶解细胞，并同时分离细胞特异性来自相同组织样本的细胞外囊泡（EV）/外泌体。作为概念证明的初始假设，我们期望观察到 AD 神经元和神经胶质细胞以及来自相同区域的 EV 中阶段介导的 tau 增加样品。大量文献记录了突触 tau 传播在阿尔茨海默病中的重要性和其他 tau 蛋白病 tau 蛋白免疫疗法已在超过 13 项研究中显示出疗效。更多最近的研究证明小胶质细胞和可能的星形胶质细胞在神经元 tau 病理学传播中发挥重要作用，但据我们所知，不存在分析同一人类大脑的多种脑细胞类型的方法。样品将来自我们经过数十年开发的 350 多个死后 AD 和老化控制皮层库尸检时冷冻保存的样本。表达人类 tau 蛋白的 tau 蛋白病小鼠模型也将被研究。目标 1 将优化流式细胞术方法来识别和分离神经元、星形胶质细胞和冷冻保存的 AD 皮层分离细胞中的小胶质细胞。目标 2 将从每个 AD 中分离出外泌体/EV 解离时的皮质样本，并分离神经元、星形胶质细胞和小胶质细胞的带有 tau 蛋白的 EV 起源。该提案将直接解决主要脑细胞类型对 AD 中 tau 进展的贡献，同时考虑每种细胞类型外泌体的作用。所提出的协议高度新颖，将最大限度地利用尸检样本和我们的流式细胞术专业知识。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Multi-Omics Analysis of Microglial Extracellular Vesicles From Human Alzheimer's Disease Brain Tissue Reveals Disease-Associated Signatures.

DOI：
10.3389/fphar.2021.766082
发表时间：
2021
期刊：
Frontiers in pharmacology
影响因子：
5.6
作者：
Cohn W;Melnik M;Huang C;Teter B;Chandra S;Zhu C;McIntire LB;John V;Gylys KH;Bilousova T
通讯作者：
Bilousova T