Exosome-mediated propagation of pathogenic tau protein

外泌体介导的致病性 tau 蛋白的增殖

基本信息

批准号：
9195881
负责人：
Tsuneya Ikezu
金额：
$ 287.1万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9195881
关键词：
Accounting Affect Alzheimer&apos s Disease American Amyloid beta-Protein Amyloid deposition Animal Model Astrocytes Biological Neural Networks Brain Brain region C57BL/6 Mouse Cells Ceramides Cerebrospinal Fluid Data Dementia Dependovirus Deposition Development Disease Disease Progression Electrophysiology (science)Frontotemporal Dementia Functional disorder Hippocampal Formation Hippocampus (Brain)Human In Vitro Inflammatory Injection of therapeutic agent Interdisciplinary Study Intervention Knock-in Mouse Knowledge Lead Lewy Body Dementia MAPT gene Medial Mediating Microglia Modeling Molecular Mus Neocortex Neurocognitive Deficit Neurofibrillary Tangles Neuronal Dysfunction Neurons Oligodendroglia Outcome Parkinson Disease Pathology Pathway interactions Patients Phagocytosis Play Preventive Prion Diseases Prions Property Pyramidal Cells Records Reporting Research Role Sphingomyelinase Staging Structure of molecular layer of cerebellar cortex Subgroup Synapses System Tauopathies Technology Testing Therapeutic Time Transgenic Mice Wild Type Mouse Work adeno-associated viral vector alpha synuclein base biocytin brain tissue cell type chronic traumatic encephalopathy cytokine dentate gyrus design effective therapy entorhinal cortex exosome in vivo inhibitor/antagonist innovation insight mouse model neurofibrillary tangle formation neuroinflammation neurophysiology neuropsychological new therapeutic target novel novel strategies overexpression patch clamp protein aggregate small hairpin RNA spatiotemporal synucleinopathy tau Proteins tau aggregation tau mutation tau-1 therapeutic target transmission process vector

项目摘要

Alzheimer's disease (AD) is the most common cause of dementia, currently affecting over 5.3 million Americans, yet lacks an effective therapy. Neurofibrillary tangles are a hallmark of AD and primarily consist of phosphorylated tau protein aggregates. Suppressing the spread of tau during the pre-symptomatic stage will potentially provide a novel preventive therapeutic approach to AD. However, the molecular and cellular mechanism of the synaptic propagation of tau is largely unknown. Exosomes are thought to be important vehicles for the spread of tau; the presence of tau proteins in the exosome fraction of cerebrospinal fluid in AD patients provides strong evidence that this mechanism is an important aspect of the pathophysiology of AD in humans. We hypothesize that microglia apposed to synapses facilitate the spread of tau via phagocytosis and secretion of tau in exosomes, and that amyloid deposition as seen in the AD brain enhances the propagation of tau through microglial activation and co-secretion of inflammatory cytokines and tau protein. Our recent studycogently demonstrate that microglia efficiently phagocytize tau aggregates and then transfer them to neurons via exosomes (Asai H et al, Nat Neurosci 2015). Our work will be powered by novel mouse models that recapitulates tau propagation: The stereotactic injection of an adeno-associated viral vector expressing neuron-specific P301L tau into the medial entorhinal cortex shows that inhibition of exosome synthesis or depletion of microglia dramatically reduces tau propagation to the dentate gyrus in vivo. To support this evidence, we showed that stereotactic injection of tau-containing exosomes from microglia successfully spread tau into dentate granular cells of dentate gyrus in wild type mice. This approach will enable us to model tau propagation using exosomes isolated from human brain tissues and non-transgenic mice. This project will focus on characterizing the role of exosomal secretion in the propagation of tau along anatomically connected neural networks using these novel mouse models with three specific aims: 1) To characterize the composition and propagation property of exosomal tau isolated from human AD brain and its potential for the propagation, 2) To determine microglia or other cell types account for exosome secretion for tau propagation, and 3) To determine how exosomal tau propagation induces neurophysiological and morphological abnormality in novel tau propagation mouse models in vivo. We anticipate that the results obtained from this proposal will lead to an entirely novel paradigm for delaying the progression of disease in AD and other tauopathies, such as frontotemporal dementia and chronic traumatic encephalopathy. Additionally, the proposed mouse models will have a wider application, including synucleinopathies (Parkinson's disease and Lewy body dementia) and prion diseases, since α-synuclein and prion also spreads via exosomes.

阿尔茨海默病 (AD) 是导致痴呆症的最常见原因，目前影响超过 530 万人美国人仍缺乏有效的治疗方法，神经原纤维缠结是 AD 的一个标志，主要包括：磷酸化 tau 蛋白聚集体在症状前阶段抑制 tau 蛋白的扩散。潜在地为 AD 提供一种新的预防性治疗方法，然而，分子和细胞。 tau 突触传播的机制在很大程度上尚不清楚，外泌体被认为很重要。 AD 脑脊液外泌体部分中存在 tau 蛋白；患者提供了强有力的证据表明该机制是 AD 病理生理学的一个重要方面人类。我们发现，与突触相对应的小胶质细胞通过吞噬作用促进 tau 蛋白的传播，外泌体中 tau 蛋白的分泌，以及 AD 大脑中所见的淀粉样蛋白沉积增强了我们最近的研究有力地证明，小胶质细胞可以有效地吞噬 tau 聚集物，然后将其转移到神经元。通过外泌体（Asai H 等人，Nat Neurosci 2015）我们的工作将由新型小鼠模型提供支持。概括 tau 传播：腺相关病毒载体表达的立体定向注射神经元特异性 P301L tau 进入内侧内嗅皮层表明，外泌体合成或抑制受到抑制小胶质细胞的消耗显着减少了体内 tau 蛋白向齿状回的传播。证据，我们表明立体定向注射来自小胶质细胞的含有 tau 的外泌体成功扩散将 tau 蛋白导入野生型小鼠齿状回的齿状颗粒细胞中，这种方法将使我们能够模拟 tau 蛋白。使用从人脑组织和非转基因小鼠中分离的外泌体进行增殖该项目将重点描述外泌体分泌在 tau 增殖中的作用。使用这些新颖的小鼠模型在解剖学上连接的神经网络具有三个特定目标：1）表征从人 AD 脑中分离的外泌体 tau 的组成和传播特性及其繁殖的潜力，2) 确定小胶质细胞或其他细胞类型负责外泌体分泌 tau 增殖，以及 3) 确定外泌体 tau 增殖如何诱导神经生理学和体内新型 tau 繁殖小鼠模型的形态异常。我们预计从该提案中获得的结果将带来一个全新的范式延缓 AD 和其他 tau蛋白病的疾病进展，例如额颞叶痴呆和慢性此外，所提出的小鼠模型将具有更广泛的应用，包括突触核蛋白病（帕金森病和路易体痴呆）和朊病毒病，因为 α-突触核蛋白和朊病毒也通过外泌体传播。