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

 描述（由申请人提供）：创伤性脑损伤（TBI）是世界范围内死亡和残疾的主要原因，是晚年痴呆和阿尔茨海默病发展的既定风险因素。神经元缠结，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，并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TBI后大脑的共同特征，但创伤性损伤后大脑中发生的使其易受tau聚集影响的变化仍然不确定，并且不存在可以预防TBI后神经变性发展的治疗。我们最近定义了一系列贯穿大脑的血管旁通道，这些通道为大脑清除神经细胞之间的废物提供了一条途径。水通道水通道蛋白-4（AQP 4）促进流体沿这些途径沿着并通过脑血管的运动，所述水通道水通道蛋白-4（AQP 4）在直接面对脑血管的星形胶质细胞膜中以高度极化的方式表达。当该通道被敲除时，沿着这些血管旁通路的流体运动沿着丧失，并且废物从脑组织的清除显著减少。Tau是主要构成神经元缠结但在静息条件下释放到脑中的蛋白质，其沿着沿着这些血管旁通路从脑中清除，而在TBI后，沿着沿着这些血管旁通路的间质溶质清除减慢。与此同时，通常定位于面向血管的星形胶质细胞过程的AQP 4失去了其极化。基于这些发现，我们认为TBI后血管周围AQP 4极化的丧失损害了间质tau蛋白的清除，促进了TBI后tau蛋白的聚集和神经退行性变。在这个建议中，我们将首先利用转基因小鼠模型，以确定是否损失血管周围AQP 4定位损害间质tau蛋白清除。然后，我们将使用体内病毒转染方法来测试TBI后AQP 4-M1变体的上调是否会导致TBI后血管周围AQP 4极化的丧失。然后，我们将在表现出自发的年龄相关的神经元缠结形成的转基因小鼠系中使用这些方法来测试血管周围AQP 4极化的丧失和间质tau清除的损害是否促进TBI后的tau聚集和神经变性。如果得到验证，那么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机制基础，并可能确定一种新的治疗方法来预防TBI后神经变性的发展。

 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.