CSF/ISF highways for tau brain clearance

用于 tau 脑清除的 CSF/ISF 高速公路

• 批准号: 8869692
• 负责人: RASHID DEANE
• 金额: $ 23.03万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8869692
• 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; 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; cerebrospinal fluid flow; chronic traumatic encephalopathy; corticobasal degeneration; dimer; extracellular; fluid flow; improved; in vivo; in vivo imaging; monomer; novel; prevent; protein aggregate; public health relevance; 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（由适用提供）：单体tau是一种细胞内微管相关蛋白，经历了逐渐过渡到tau丝（神经纤维纤维缠结（NFTS）（NFTS）（NFTS）的不溶性骨料，Tauopathies，Tauopathies的特征，例如最近释放的iSOMENS ITOMENS ITOMERS。在有利的条件下，健康的年轻大脑可以增强细胞外Tau骨料的形成，但是，来自ISF的单体TAU清除率在AD中是未知的。簇状的星形胶质细胞。该系统由三个主要途径组成：（1）通过para-Arachnoid CSF的影响，（2）星形胶质细胞通道蛋白4（AQP4）对流的对流，依赖于（3）通过Para-venos consim consic cover consim consim。从CSF和脑淋巴系统中从CSF中清除，这在衰老和AQP4 KO小鼠中降低了，但是，短纤维在大脑中保留了更长的时间。 1）表征小鼠CSF和脑ISF的TAU清除机制，以及2）评估衰老和AQP4对脑清除tau蛋白质物种的影响。 125i-TAU分布和进化的动力学将通过使用我们的非侵入性技术并在注射后与外部计数器记录大脑放射性来确定。我们将使用体内实时2-Photon和共聚焦显微镜来描述Tau，CSF/ISF交换和清除途径的影响。宫颈淋巴清除动力学将使用宫颈淋巴视频和节点的实时体内成像进行分析。我们预计数据将表明TAU（单体>原纤维）通过CSF/ISF交换和对流ISF流以及宫颈淋巴清除。通过衰老和AQP4 - / - 小鼠，通过这两种途径的清除率将降低。由于细胞结合素，tau纤维将在大脑中保留更长的时间。这些研究可能导致完全新颖的tau清除率，从而通过改善TAU的糖/淋巴清除率和其他有毒分子来减慢甚至可以防止与AD相关的神经认知下降。