Pathogenicity of neuronally-derived tau in exosomes

项目摘要/摘要 阿尔茨海默病(AD)是痴呆症最常见的形式，其神经病理特征为 β-淀粉样蛋白(A-β)斑块和神经原纤维缠结(NFT)的存在 磷酸化的tau蛋白。AD的对症治疗已经开发出来，但有效的疾病-- 修改干预措施仍然是必要的。已经确定了治疗疾病药物的靶点，但结果是 临床试验的结果一直令人失望。AD的生物标志物可能会改进临床试验设计和分析， 增加了药物开发成功的可能性。AD中Tau释放的确切机制是 不完全了解，但一些研究表明，牛磺酸可能是以聚集形式释放的 囊泡或无膜。其中，最近的研究表明，Tau的致病形式可能在 L1细胞黏附蛋白(LI CAM)阳性的外体小泡，表明它们已脱落 从神经细胞进入脑脊液和血液。没有特别的准备和 对于外切体的分离，这些神经源性的外切体(L1NE)含有Tau不是 在血液中可以检测到。我们推测，Tau在外体中的运输从中枢神经系统到脑脊液和/或血液 是识别AD分期的重要途径，可用于识别处于临床前阶段的患者 病理学正在发展，没有看到明显的认知影响。

Project Summary/Abstract Alzheimer's disease (AD) is the most common form of dementia and is characterized neuropathologically by the presence of β-amyloid (Aβ)-containing plaques and neurofibrillary tangles (NFTs) composed of phosphorylated tau protein. Symptomatic treatments for AD have been developed, but effective disease- modifying intervention is still needed. Targets have been identified for disease-modifying drugs, but the results of clinical trials have been disappointing. Biomarkers of AD may improve clinical trial design and analysis, increasing the likelihood of successful drug development. The precise mechanisms of Tau release in AD are not completely understood, however some studies indicates that Tau might be released as aggregates in clear vesicles or membrane free. Of them, recent studies suggest that pathogenic forms of Tau might be released in exosomal vesicles that are positive for the L1 cell adhesion protein (LI CAM), suggesting that they are shed from neuronal cells from where they can traffic to the CSF and blood. Without specific preparation and handling for isolation of exosomes, these neuronally-derived exosomes (L1NE) containing Tau are not detectible in blood. We hypothesize that the trafficking of Tau in exosomes from the CNS to CSF and/or blood is an important pathway in identifying stages of AD and can serve to identify patients in preclinical stages when pathology is developing and no overt cognitive effects are seen.