Exosome-mediated propagation of pathogenic tau protein

外泌体介导的致病性 tau 蛋白的增殖

• 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
• 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' 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

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 美国人却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 蛋白的传播将 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 突触传播的机制很大程度上未知。外泌体被认为很重要 传播 tau 蛋白的载体； 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。 我们假设与突触相邻的小胶质细胞通过吞噬作用促进 tau 蛋白的扩散， 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 tau 通过小胶质细胞激活并共同分泌炎症细胞因子和 tau 蛋白。我们最近的研究有力地证明小胶质细胞有效地吞噬 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）。我们的工作将由新颖的鼠标模型提供支持 概括 tau 传播：表达腺相关病毒载体的立体定向注射 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 小胶质细胞的耗竭极大地减少了 tau 蛋白在体内向齿状回的传播。为了支持这个 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 tau 蛋白进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对 tau 进行建模 使用从人脑组织和非转基因小鼠中分离的外泌体进行繁殖。该项目将重点描述外泌体分泌在 tau 蛋白增殖中的作用 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 增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 外伤性脑病。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。