CSF/ISF highways for tau brain clearance

用于 tau 脑清除的 CSF/ISF 高速公路

基本信息

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
项目类别：
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&apos 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

项目摘要

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（申请人证明）：单体tau是一种细胞内微管相关蛋白，经历了tau丝的A. le骨料（Neurofibrillary Tangles（NFTS）（NFTS），Tauopathies，例如Alzheimer氏病（AD）的特征。 TAU从健康的年轻大脑中释放到室间液中，这可以增强细胞外tau的形成。在血管周围的皮质变性，与星形胶质斑块和Tufft形的星形胶质细胞相关。 CSF/ISF在减少TAU的积累中至关重要。 Aquaporin 4（AQP4）依赖于大脑的对流流，（3）通过para -venos of -deflux，可以通过宫颈淋巴清除CSF。脑脑大脑脑大脑通过gllymphatic和aD宫颈淋巴系统，并且在Glymphatic/lymphatic System中与AQP4 KO小鼠的减少和脑膜化有关。在这些系统中，IS累积了。肠内注射后，我们将在体内实时2光子和共聚焦显微镜来描述Tauuu，CSF/ISF交换和颈淋巴清除率的涌入。 c船和节点。由于细胞结合而引起的大脑。