Role of perivascular aquaporin-4 polarization in post-traumatic neurodegeneration

 描述(申请人提供)：创伤性脑损伤(TBI)是世界范围内导致死亡和残疾的主要原因，也是老年痴呆症和阿尔茨海默病在晚年发展的既定风险因素。神经原纤维缠结是由细胞内蛋白tau组成的聚集体，是阿尔茨海默病大脑的标志之一，被认为是导致这种情况下神经元死亡的原因。虽然这些tau聚集体是脑损伤后的一个共同特征，但创伤后脑内发生的使其易受tau聚集影响的变化仍未明确，目前还没有可以防止脑损伤后神经变性发展的治疗方法。我们最近定义了一系列贯穿大脑的血管旁通道，为大脑提供了一条从神经细胞之间清除废物的途径。水通道蛋白4(AQP4)促进了液体沿这些途径和通过脑间质的运动，AQP4在直接面对脑血管系统的星形胶质细胞膜上以高度极化的方式表达。当这一通道被破坏时，沿着这些血管旁通道的液体运动就会丢失，大脑间质中废物的清除也会显著减少。Tau是一种主要构成神经原纤维缠结的蛋白质，在静息状态下被释放到间质中，它沿着这些血管旁途径从大脑中清除，而在脑损伤后，沿着这些血管旁途径的间质溶质清除速度减慢。与此同时，通常定位于面向血管的星形胶质细胞突起的AQP4失去了极化。基于这些发现，我们认为，脑损伤后血管周围AQP4极化的丧失损害了间质tau的清除，促进了tau的聚集和神经变性。在这个方案中，我们将首先利用转基因小鼠模型来确定血管周围AQP4定位的丢失是否会损害间质tau的清除。然后，我们将使用体内病毒转染的方法来测试脑损伤后AQP4-M1变体的上调是否导致脑损伤后血管周围AQP4极化的丧失。然后，我们将在表现出自发的与年龄相关的神经纤维缠结形成的转基因小鼠中使用这些方法来测试血管周围AQP4极化的丧失和间质tau清除的障碍是否促进了脑损伤后tau的聚集和神经变性。如果得到证实，这些研究可能为创伤后大脑对tau聚集和神经变性的脆弱性提供一个机制基础，并可能找到防止脑外伤后神经变性发展的新的治疗方法。

 DESCRIPTION (provided by applicant): Traumatic brain injury (TBI), a leading cause of death and disability worldwide, is an established risk factor for the development of dementia and Alzheimer's disease later in life. Neurofibrillary tangles, aggregates composed of the intracellula protein tau, are one of the hallmarks of the Alzheimer's disease brain and are thought to cause the death of neurons in this condition. Although these tau aggregates are a common feature of the brain after TBI, the changes that occur in the brain after traumatic injury that make it vulnerable to tau aggregation remain undefined and no treatments exist that can prevent the development of neurodegeneration after TBI. We have recently defined a series of paravascular channels throughout the brain that provide an avenue for the brain to clear wastes from between neural cells. Fluid movement along these pathways and through the brain interstitium is facilitated by the water channel aquaporin-4 (AQP4) which is expressed in a highly polarized manner in astrocyte membranes that directly face the brain vasculature. When this channel is knocked out, fluid movement along these paravascular pathways is lost and the clearance of wastes from the brain interstitium is markedly reduced. Tau, the protein that chiefly makes up neurofibrillary tangles yet is released into the interstitium under resting conditions, is cleared from the brain along these paravascular pathways, while interstitial solute clearance along these paravascular pathways is slowed after TBI. At the same time, AQP4, which is normally localized to vessel-facing astrocyte processes, loses its polarization. Based on these findings, we propose that the loss of perivascular AQP4 polarization after TBI impairs interstitial tau clearance, promoting tau aggregation and neurodegeneration after TBI. In this proposal, we will first utilize a transgenic mouse model to determine whether loss of perivascular AQP4 localization impairs interstitial tau clearance. We will then use an in vivo viral transfection approach to test whether upregulation of the AQP4-M1 variant after TBI causes the loss of perivascular AQP4 polarization after TBI. We will then use these approaches in a transgenic mouse line exhibiting spontaneous age-related neurofibrillary tangle formation to test whether loss of perivascular AQP4 polarization and impairment of interstitial tau clearance promote tau aggregation and neurodegeneration after TBI. If validated, then these studies may provide a mechanistic basis for the vulnerability of the post-traumatic brain to tau aggregation and neurodegeneration, and may identify a new therapeutic approach to preventing the development of neurodegeneration after TBI.