Pathogenicity of neuronally-derived tau in exosomes

外泌体中神经源性 tau 蛋白的致病性

• 批准号: 9336219
• 负责人: Robert A Rissman
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336219
• 关键词: Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Antibodies; Autopsy; Axonal Transport; Behavioral; Binding; Binding Proteins; Biochemical; Biological Assay; Biological Markers; Blood; Brain; CD81 gene; Caspase; Cell Adhesion Molecules; Cells; Cleaved cell; Clinical Trials; Clinical Trials Design; Cognitive; Collaborations; Cytoskeleton; Data; Dementia; Detection; Disease; Enzyme-Linked Immunosorbent Assay; Hematological Disease; Human; Injectable; Injection of therapeutic agent; Intervention; Knockout Mice; Mass Spectrum Analysis; Membrane; Microtubules; Neurofibrillary Tangles; Neurons; Organ; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Plasma; Play; Preparation; Protein Isoforms; Proteins; Role; Sampling; Seeds; Severity of illness; Structure; Toxic effect; Transgenic Animals; Transgenic Mice; Vesicle; Wild Type Mouse; Work; alpha Tubulin; biobank; drug development; exosome; experimental study; follow-up; improved; in vivo; pre-clinical; prion-like; promoter; symptom treatment; tau Proteins; tau aggregation; tau mutation; tau phosphorylation; tau-1; trafficking

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.

项目概要/摘要 阿尔茨海默病 (AD) 是痴呆症最常见的形式，其神经病理学特征为 含有 β-淀粉样蛋白 (Aβ) 的斑块和神经原纤维缠结 (NFT) 的存在 磷酸化 tau 蛋白已开发出针对 AD 的治疗方法，但仍是有效的疾病治疗方法。 仍然需要改变干预措施，以改善疾病的药物的目标已经确定，但结果还不错。 AD 的生物标志物可能会改善临床试验的设计和分析， 增加药物开发成功的可能性 AD 中 Tau 释放的确切机制是 尚未完全了解，但一些研究表明 Tau 可能以透明的聚集体形式释放 其中，最近的研究表明，Tau 蛋白的致病形式可能会释放在其中。 L1 细胞粘附蛋白 (LI CAM) 呈阳性的外泌体囊泡，表明它们已脱落 来自神经元细胞，它们可以从那里运输到脑脊液和血液，无需特殊的准备和处理。 处理分离外泌体时，这些含有 Tau 的神经源性外泌体 (L1NE) 不 我们追踪外泌体中 Tau 蛋白从 CNS 转运至脑脊液和/或血液的情况。 是识别 AD 阶段的重要途径，可用于识别处于临床前阶段的患者 病理学正在发展，没有观察到明显的认知影响。

项目成果

Blood-based biomarkers in Alzheimer disease: Current state of the science and a novel collaborative paradigm for advancing from discovery to clinic.

阿尔茨海默病的血液生物标志物：科学现状和从发现到临床的新型合作范例。

• 发表时间: 2017-01
• 作者: O'Bryant, Sid E;Mielke, Michelle M;Rissman, Robert A;Lista, Simone;Vanderstichele, Hugo;Zetterberg, Henrik;Lewczuk, Piotr;Posner, Holly;Hall, James;Johnson, Leigh;Fong, Yiu;Luthman, Johan;Jeromin, Andreas;Batrla;Villar
• 通讯作者: Villar