Exosome-mediated propagation of pathogenic tau protein

阿尔茨海默病(AD)是痴呆症最常见的原因，目前影响着530多万人 美国人，但缺乏有效的疗法。神经原纤维缠结是阿尔茨海默病的一个标志，主要包括 磷酸化的tau蛋白聚集体。在症状前期抑制tau的传播将会 有可能为AD提供一种新的预防和治疗方法。然而，分子和细胞 Tau的突触传播机制在很大程度上是未知的。外显子被认为是重要的 Tau蛋白传播的载体；AD患者脑脊液外体部分中tau蛋白的存在 患者提供了强有力的证据，表明这一机制是AD病理生理学的一个重要方面 人类。 我们假设，与突触相对的小胶质细胞通过吞噬作用促进tau的传播，并 在外体中分泌tau，以及在AD大脑中看到的淀粉样蛋白沉积增强了 通过激活小胶质细胞，共同分泌炎性细胞因子和tau蛋白。我们最近的研究表明，小胶质细胞有效地吞噬tau聚集体，然后将它们转移到神经元。 通过Exosome(Asai H等人，NAT Neurosci 2015)。我们的工作将由新的鼠标模型提供动力， 概述tau增殖：立体定向注射表达Tau基因的腺相关病毒载体 神经元特异性P301L tau进入内侧内嗅皮质表明，抑制外体合成或 在活体中，小胶质细胞的耗竭显著减少了tau向齿状回的繁殖。为了支持这一点 证据表明，立体定向注射来自小胶质细胞的含有tau的外切体成功地扩散了 Tau在野生型小鼠齿状回的齿状颗粒细胞。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分离的外切体进行繁殖。这项计划将集中在表征外体分泌在tau的繁殖过程中的作用。 使用这些新的小鼠模型的解剖连接的神经网络具有三个特定目的：1) 人阿尔茨海默病及其脑组织外体tau的组成和增殖特性研究 繁殖的潜力，2)确定小胶质细胞或其他细胞类型解释外切体分泌 Tau繁殖，以及3)确定外体tau繁殖如何诱导神经生理学和 新的tau繁殖小鼠体内模型的形态异常。 我们预计，从这一提议中获得的结果将导致一种全新的模式 延缓阿尔茨海默病和其他神经官能症的疾病进展，如额颞叶痴呆和慢性 创伤性脑病。此外，建议的鼠标模型将有更广泛的应用，包括 突触核病(帕金森氏病和路易体痴呆)和Pron病，因为α-突触核蛋白和 Pron也通过外切体传播。

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.