CSF/ISF highways for tau brain clearance

用于 tau 脑清除的 CSF/ISF 高速公路

• 批准号: 9052110
• 负责人: RASHID DEANE
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9052110
• 关键词: Age; Aging; Alzheimer' s Disease; Amyloid; Arachnoid mater; Astrocytes; Binding; Blood Vessels; Brain; Brain Injuries; Cells; Cerebrospinal Fluid; Cervical; Cervical lymph node group; Confocal Microscopy; Cysteine; Data; Deposition; Drainage procedure; Excision; Failure; Frontotemporal Dementia; Health; Injection of therapeutic agent; Intercellular Fluid; Kinetics; Lead; Lymph; Lymphatic; Lymphatic System; Lymphatic vessel; Metabolic Clearance Rate; Microtubule-Associated Proteins; Molecular Weight; Mus; Neurocognitive Deficit; Neurofibrillary Tangles; Pathway interactions; Play; Process; Proteins; Radioactivity; Role; Route; Shapes; Site-Directed Mutagenesis; Stroke; System; Tauopathies; Techniques; Testing; Time; Traumatic Brain Injury; Venous; age effect; age related; analytical tool; aquaporin 4; arteriole; bindin; brain parenchyma; cerebrospinal fluid flow; chronic traumatic encephalopathy; corticobasal degeneration; dimer; extracellular; fluid flow; glymphatic system; improved; in vivo; in vivo imaging; monomer; novel; prevent; protein aggregate; relating to nervous system; research study; tau Proteins; tau aggregation; transmission process; two-photon; uptake

 DESCRIPTION (provided by applicant): Monomeric tau, an intracellular microtubule-associated protein, undergoes a progressive transition to insoluble aggregates of the tau filaments (neurofibrillary tangles (NFTs), a feature of tauopathies, such as Alzheimer's disease (AD). Recently it was shown that wild type monomeric tau is released into the interstitial fluid (ISF) from healthy normal young brains which, under favorable conditions, could enhance the formation of extracellular tau aggregates. However, the mechanism of monomeric tau clearance from the ISF is unknown. In AD, aggregated tau is present in the perivascular space, and tau oligomers are associated with arterioles. In corticobasal degeneration, tau is deposited around blood vessels and associated with astrocytic plaques and tuft-shaped astrocytes. In AD, levels of cerebrospinal fluid (CSF) tau are increased. These observations may suggest possible clearance routes from brain. Since monomeric tau is the precursor of the misfolded and aggregated tau, its removal from the CSF/ISF is critical in reducing tau accumulation. Recently, the glymphatic system was shown to play a major role in clearance of by-products of neural activity. This system consists of three main pathways: (1) influx of sub-arachnoid CSF via the para-arterial space, (2) astrocytic aquaporin 4 (AQP4)-dependent convective flow of brain ISF, and (3) efflux via para-venous clearance. In addition, CSF can be cleared from brain via the cervical lymph. Our preliminary data show that monomeric tau was cleared from the CSF and from brain parenchyma via the glymphatic and cervical lymphatic systems, and that this was reduced with aging and in Aqp4 ko mice. However, short fibrils were retained longer in brain. We hypothesize that the glymphatic/lymphatic systems are critical for brain-wide clearance of tau and that age-related failure in these systems contributes to its accumulation. There are two aims, 1) Characterization of the tau clearance mechanisms from CSF and brain ISF in mice, and 2) Evaluating the effects of aging and AQP4 on the clearance of tau protein species from brain. The kinetics of 125I-tau distribution and elimination will be determined by using our non-invasive technique and recording brain radioactivity with an external counter after intracisternal injection. We will use in vivo real-time 2-photon and confocal microscopy to delineate the influx of tau, CSF/ISF exchange and clearance pathways. Cervical lymph clearance kinetics will be analyzed using real-time in vivo imaging of the cervical lymphatic vessels and nodes. We expect that the data will show that tau (monomer >fibril) is cleared via CSF/ISF exchange and convective ISF flow, and by the cervical lymph. Clearance via both pathways will be reduced with aging and in Aqp4-/- mice. Tau fibrils will be retained longer in brain due to cellular bindin. These studies may lead to entirely novel targets for tau clearance to slow or even prevent AD related neurocognitive decline by improving glymphatic/lymphatic clearance of tau, and other toxic molecules.

 描述（由申请人提供）：单体 tau 是一种细胞内微管相关蛋白，逐渐转变为不溶性 tau 丝聚集体（神经原纤维缠结 (NFT)，这是 tau 病的一个特征，例如阿尔茨海默氏病 (AD)。最近发现，野生型单体 tau 会从细胞中释放到间质液 (ISF) 中。 健康正常的年轻大脑在有利的条件下可以增强细胞外 tau 蛋白聚集体的形成。然而，单体 tau 从 ISF 清除的机制尚不清楚。在 AD 中，聚集的 tau 蛋白存在于血管周围空间，并且 tau 蛋白寡聚体与小动脉相关。在皮质基底节变性中，tau 蛋白沉积在血管周围并与星形胶质细胞斑块和 簇状星形胶质细胞。在 AD 中，脑脊液 (CSF) tau 蛋白水平升高。这些观察结果可能表明大脑可能的清除途径。由于单体 tau 是错误折叠和聚集 tau 的前体，因此将其从 CSF/ISF 中去除对于减少 tau 积累至关重要。最近，类淋巴系统被证明在清除副产物方面发挥着重要作用。 神经活动。该系统由三个主要途径组成：(1) 蛛网膜下脑脊液通过动脉旁间隙流入，(2) 星形细胞水通道蛋白 4 (AQP4) 依赖性脑 ISF 对流，以及 (3) 通过静脉旁间隙流出。此外，脑脊液可以通过颈部淋巴从大脑中清除。我们的初步数据表明单体 tau 蛋白通过类淋巴系统和颈淋巴系统从脑脊液和脑实质中清除，并且这种情况随着年龄的增长而减少，并且在 Aqp4 ko 小鼠中。然而，短原纤维在大脑中保留的时间更长。我们假设类淋巴系统对于全脑 tau 蛋白的清除至关重要，并且这些系统中与年龄相关的故障导致了 tau 蛋白的积累。有两个 目标，1) 表征小鼠 CSF 和脑 ISF 的 tau 清除机制，2) 评估衰老和 AQP4 对脑中 tau 蛋白种类清除的影响。 125I-tau 分布和消除的动力学将通过使用我们的非侵入性技术并在脑池内注射后用外部计数器记录脑放射性来确定。我们将使用体内实时 2 光子和共聚焦显微镜来描绘 tau 蛋白的流入、CSF/ISF 交换和清除途径。将使用颈部淋巴管和淋巴结的实时体内成像来分析颈部淋巴清除动力学。我们预计数据将显示 tau（单体>原纤维）通过 CSF/ISF 交换和对流 ISF 流以及颈部淋巴被清除。在 Aqp4-/- 小鼠中，通过这两种途径的清除率都会随着年龄的增长而减少。由于细胞结合，Tau 原纤维将在大脑中保留更长时间。这些研究可能会产生全新的 tau 蛋白清除靶点，通过改善 tau 蛋白和其他有毒分子的类淋巴/淋巴清除率来减缓甚至预防 AD 相关的神经认知衰退。