Pathogenicity of neuronally-derived tau in exosomes

项目总结/摘要 阿尔茨海默病（AD）是痴呆的最常见形式，并且在神经病理学上的特征在于： 存在含β-淀粉样蛋白（Aβ）的斑块和神经纤维缠结（NFT）， 磷酸化tau蛋白。AD的对症治疗已经开发出来，但有效的疾病- 仍然需要修改干预措施。已经确定了疾病修饰药物的靶点，但结果 临床试验结果令人失望。AD的生物标志物可以改善临床试验设计和分析， 增加药物开发成功的可能性。AD中Tau释放的确切机制是 尚未完全理解，然而，一些研究表明，Tau可能作为聚集体释放， 囊泡或无膜。其中，最近的研究表明，Tau的致病形式可能会在 外泌体囊泡对L1细胞粘附蛋白（LI CAM）呈阳性，表明它们脱落 从神经元细胞到脑脊液和血液。没有具体的准备， 为了分离外泌体，这些含有Tau的神经元来源的外泌体（L1 NE）不是 在血液中可以检测到我们假设Tau在外泌体中从CNS到CSF和/或血液的运输 是识别AD阶段的重要途径，并且可以用于识别处于临床前阶段的患者， 病理学正在发展，没有观察到明显的认知影响。

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.