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

血管周围水通道蛋白 4 极化在创伤后神经变性中的作用

基本信息

批准号：
9309096
负责人：
Jeffrey J Iliff
金额：
$ 34.25万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
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：
2015-09-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9309096
关键词：
Age-Years Alzheimer&apos s Disease Astrocytes Attention Biochemical Brain Brain Concussion Brain Diseases Brain Injuries Cause of Death Cerebrovascular system Cerebrum Chronic Clinical Data Dementia Dependovirus Development Event Exhibits Exposure to Face Failure Gene Delivery Impairment Infusion procedures Injury Knock-out Knockout Mice Label Lead Life Liquid substance MAPT gene Membrane Messenger RNA Microdialysis Military Personnel Movement Mus Nerve Degeneration Neurofibrillary Tangles Neurons Pathology Pathway interactions Patients Prevalence Process Proteins RNA Interference Radio Reporting Research Rest Risk Risk Factors Role Series Services Sports Survivors System Testing Time Transcript Transfection Transgenic Mice Traumatic Brain Injury Traumatic injury United States Up-Regulation Variant Viral age related aquaporin 4 base brain cell brain parenchyma chronic traumatic encephalopathy disability extracellular glymphatic system in vivo interstitial knock-down mild traumatic brain injury mouse model neurofibrillary tangle formation neuron loss novel novel therapeutic intervention prevent protein aggregate public health relevance small hairpin RNA solute syntrophin alpha1 tau Proteins tau aggregation therapeutic target wasting water channel

项目摘要

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.

描述（由申请人提供）：创伤性脑损伤 (TBI) 是全世界死亡和残疾的主要原因，也是晚年发展为痴呆和阿尔茨海默病的既定危险因素。神经原纤维缠结是由细胞内 tau 蛋白组成的聚集体，是阿尔茨海默病大脑的标志之一，被认为会导致这种情况下的神经元死亡。尽管这些 tau 蛋白聚集是 TBI 后大脑的一个常见特征，但创伤性损伤后大脑中发生的变化使其容易受到 tau 蛋白聚集的影响，这一变化仍未明确，而且尚无治疗方法可以预防 TBI 后神经退行性疾病的发展。我们最近在整个大脑中定义了一系列血管旁通道，为大脑清除神经细胞之间的废物提供了途径。水通道水通道蛋白 4 (AQP4) 促进液体沿着这些通路并通过脑间质运动，水通道蛋白 4 在直接面向脑脉管系统的星形胶质细胞膜中以高度极化的方式表达。当这个通道被破坏时，沿着这些血管旁通路的液体运动就会消失，大脑间质的废物清除也会明显减少。 Tau 蛋白主要构成神经原纤维缠结，但在静息条件下会释放到间质中，并沿着这些血管旁通路从大脑中清除，而 TBI 后沿着这些血管旁通路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，我们提出 TBI 后血管周围 AQP4 极化的丧失会损害间质 tau 清除，促进 TBI 后 tau 聚集和神经变性。在本提案中，我们将首先利用转基因小鼠模型来确定血管周围 AQP4 定位的丧失是否会损害间质 tau 清除。然后，我们将使用体内病毒转染方法来测试 TBI 后 AQP4-M1 变体的上调是否会导致 TBI 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原纤维缠结形成的转基因小鼠系中使用这些方法，以测试血管周围 AQP4 极化的丧失和间质 tau 清除的受损是否会促进 TBI 后 tau 聚集和神经变性。如果得到验证，这些研究可能为创伤后大脑对 tau 蛋白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。