The glymphatic system, a new concept in glia biology

在躯体组织中，大脑和脊髓几乎是独一无二的，缺乏淋巴系统。尽管有很高的 神经组织的代谢活性和脆性，目前还没有有效的理解 将间质液体和废物从中枢神经系统中移除。我们的初步分析，基于体内的两个- 光子成像显示，输送到脑脊液的低分子示踪剂循环速度惊人地快 通过老鼠的大脑，并沿着令人惊讶的解剖学路线做到这一点。这包括动脉旁的流入。 一条跨胶质实质内的间质血流路径和一条静脉旁流出路径。在内部- 实质途径，星形胶质细胞支持流经大脑间质的对流流体，因为 星形胶质细胞水通道AQP4的缺失大大减少了沿着这些途径的总示踪剂流量。给定 由这一途径支持的液体的持续运动及其对星形细胞水的严重依赖 运输，我们建议这个系统--我们在这里称之为‘字形系统’--从属于一个 与外周淋巴系统同源的功能，是清除代谢废物所必需的 来自CNS的产品。AIM 1将使用双光子活体显微镜来评估空间动力学和 荧光团标记示踪剂清除的时间动力学。通过系统地比较两种方法的效果 分子大小或表面电荷的修饰在示踪剂清除时，我们将定义基本的传输 淋巴系统的性质。目的2将扩大初步观察，即衰老小鼠表现出 淋巴系统功能显著下降，并评估与年龄相关的动脉壁抑制的作用 脉动和由此导致的沿动脉旁路径的对流流入减少和全球淋巴功能。 目标3提出诱导星形细胞AQP4水通道或缝隙连接(Cx43/Cx30)的敲除 将减缓实质对流流体的流动，并在全球范围内抑制示踪剂清除。AIM 4测试了这个命题 AQP4或Cx43/Cx30缺失导致的跨星形胶质细胞液体运动的抑制将放缓 清除外源性A？，从而加强与年龄相关的淀粉样斑块的形成。我们预测 减缓星形细胞实质液体流动将加速血管旁淀粉样蛋白沉积，这在饲料中- 前进的方式将进一步降低液氮系统清除废品的效率。 据我们所知，这些研究是系统地定义这些机制的第一次尝试 参与从整个器官水平上清除大脑中的代谢废物。双光子 通过慢性颅窗的成像将允许实时成像示踪剂清除，而 关键星形胶质细胞膜蛋白可诱导缺失的转基因小鼠将确立 淋巴运输中的星形胶质细胞。总而言之，这些研究将为我们提供对 促进与年龄相关的神经毒性代谢废物积累的机制和定义 星形胶质细胞的新的，可能非常重要的功能特性。

Virtually unique among somatic tissues, the brain and spinal cord lack a lymphatic system. Despite the high metabolic activity and fragility of neural tissue, there exists no effective understanding of the means by which interstitial fluid and waste products are removed from the CNS. Our preliminary analysis, based on in vivo two- photon imaging, shows that low molecular weight tracers delivered to the CSF circulate surprisingly rapidly through the mouse brain, and do so along a surprising anatomical route. This consists of a para-arterial inflow path, a trans-glial intra-parenchymal path of interstitial flow, and a para-venous outflow path. Within the intra- parenchymal pathway, astrocytes support convective fluid currents through the brain interstitial space, as deletion of the astrocytic water channel AQP4 sharply reduces overall tracer flow along these routes. Given the continuous movement of fluid supported by this pathway, and its critical dependence upon astrocytic water transport, we propose that this system - which we designate here the 'glymphatic system' - subserves a function homologous to the peripheral lymphatic system, and is essential for the clearance of metabolic waste products from the CNS. Aim 1 will use 2-photon in vivo microscopy to assess the spatial dynamics and temporal kinetics of fluorophore-tagged tracer clearance. By systematically comparing the effect of modifications of molecular sizes or surface charge upon tracer clearance, we will define the basic transport properties of the glymphatic system. Aim 2 will extend the preliminary observation that aged mice exhibit a striking decline in glymphatic system function, and evaluate the role of age-related suppression of arterial wall pulsation and resulting reduced convective inflow along the para-arterial path and global glymphatic fucntion. Aim 3 proposes that induced knock-out of either astrocytic AQP4 water channels or gap junctions (Cx43/Cx30) will slow parenchymal convective fluid flow and globally suppress tracer clearance. Aim 4 tests the proposition that suppression of trans-astroglial fluid movement resulting from AQP4 or Cx43/Cx30 deletion will slow clearance of exogenous A¿ and thereby potentiate age-related amyloid plaque formation. We predict that slowing astrocytic parenchymal fluid flow will accelerate paravascular amyloid deposition, which in a feed- forward manner will further reduce the efficiency of clearance of waste products by the glymphatic system. To our knowledge, these studies represent the first attempt to systematically define the mechanisms involved in the clearance of metabolic waste products from the brain on a whole-organ level. Two-photon imaging of through chronic cranial windows will allow imaging of tracer clearance in real time, whereas transgenic mice with inducible deletion of key astroglial membrane proteins will establish the functional role of astrocytes in glymphatic transport. Combined, these studies will provide fundamental insight into the mechanisms contributing to age-related accumulation of neurotoxic metabolic waste products and define novel, and likely highly important, functional properties of astrocytes.