Role of Cerebrovascular cells in tau processing following traumatic brain injury

脑血管细胞在脑外伤后 tau 蛋白加工中的作用

• 批准号: 10266032
• 负责人: Corbin Bachmeier
• 金额: --
• 依托单位: BAY PINES VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266032
• 关键词: Affect; Alzheimer' s Disease; Animals; Biological; Biological Process; Blood Vessels; Brain; Brain Injuries; Cell Density; Cells; Cerebrovascular system; Chronic; Clinical; Craniocerebral Trauma; Cytoplasmic Protein; Disease; Disease Progression; Drainage procedure; Environment; Evolution; Extracellular Space; Hippocampus (Brain); Human; Injury; Investigation; Liquid substance; Mediator of activation protein; Metabolism; Microglia; Modeling; Movement; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurons; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Pericytes; Phagocytes; Play; Prevalence; Process; Public Health; Reporting; Risk; Role; Smooth Muscle Myocytes; Specimen; Tauopathies; Testing; Transgenic Organisms; Trauma; Traumatic Brain Injury; Veterans; Wild Type Mouse; Work; brain cell; cerebrovascular; chronic traumatic encephalopathy; combat; extracellular; glymphatic system; hyperphosphorylated tau; improved; mild traumatic brain injury; military veteran; mouse model; neurodegenerative phenotype; novel strategies; prevent; solute; tau Proteins; tau aggregation; tau-1; treatment strategy; uptake; vascular contributions; welfare; wound

One of the prominent pathological features of traumatic brain injury (TBI) is the accumulation of hyperphosphorylated and aggregated tau species in the brain. Tau is a cytoplasmic protein which is believed to be restricted to the intracellular compartment of neurons. However, several recent studies have investigated the existence and role for tau in the extracellular compartments of the brain, and have indicated that increased levels of monomeric tau in the extracellular environment play a major role in the pathogenesis of neurodegenerative tauopathies. In fact, it has been reported that extracellular tau levels in the brain correlate with clinical outcome in TBI. Despite the prevalence and potential importance of extracellular tau in neurodegenerative disease, there is little understanding of how extracellular tau is processed and eliminated from the brain. Our studies demonstrate that brain vascular mural cells (pericytes and smooth muscle cells) are involved in the processing and elimination of extracellular tau. Consistent with other neurodegenerative disorders, we observed a progressive decline in cerebrovascular mural cell expression following repetitive mild TBI (r-mTBI) in mice. Moreover, isolated brain vessels from r-mTBI animals were less able to internalize and process tau than non-injured animals. To our knowledge, these are the first studies to observe perturbations in mural cell expression and tau processing in the context of brain trauma. Importantly, alongside the mural cell disruptions in our mouse r-mTBI model, we observed an accumulation of total tau, phosphorylated tau, and oligomeric tau species in the brain. Additionally, we showed that tau elimination from the brain is reduced in transgenic mural-cell depleted animals compared to wild-type mice. We propose that brain vascular mural cells serve as a pathway for processing and eliminating tau from extracellular brain fluids and that disruption of these cells in TBI leads to tau pathology and neurodegeneration. The objective of this project is to determine the contribution of brain vascular mural cells to the tau pathology observed in TBI. The specific aims of this proposal are, 1) examine mural cell status and tau pathology in mural-cell depleted animals and human TBI brains, 2) evaluate the role of mural cells in tau degradation and elimination and the impact of r-mTBI on these processes, and 3) determine the role of mural cells in paravascular (glymphatic) tau clearance and perivascular tau drainage from the brain following r-mTBI. To determine mural cell status following TBI, tau uptake and various mural cell markers will be examined in isolated cerebrovasculature from mural-cell depleted animals and human TBI brain specimens. To understand the influence of mural cells on tau disposition, tau degradation will be evaluated in isolated brain vasculature from r-mTBI animals and tau elimination from the brain will be examined in mural-cell depleted animals and r-mTBI mice. Lastly, to understand the impact of mural cells on extracellular tau movement in brain fluids following r-TBI, we will examine both paravascular (glymphatic) tau clearance and perivascular tau drainage from the brain in mural-cell depleted animals and r- mTBI mice. The proposed studies will advance our understanding of tau processing and elimination from extracellular brain fluids and determine the contribution of brain vascular mural cells to tau pathology and the neurodegenerative phenotype following TBI.

创伤性脑损伤(TBI)的一个显著病理特征是脑组织中 大脑中过度磷酸化和聚集的tau物种。Tau是一种细胞质蛋白，被认为是 仅限于神经元的细胞内隔间。然而，最近的几项研究调查了 Tau在脑细胞外室的存在和作用，并表明它增加了 细胞外环境中单体tau的水平在慢性粒细胞白血病的发病机制中起重要作用。 神经退行性变态反应。事实上，据报道，大脑中细胞外tau的水平与 与脑外伤的临床转归有关。尽管细胞外tau的普遍存在和潜在的重要性在 神经退行性疾病，对细胞外tau是如何处理和消除的了解很少 来自大脑。我们的研究表明，脑血管壁细胞(周细胞和平滑肌细胞) 参与细胞外tau的加工和消除。与其他神经退行性疾病一致 我们观察到反复轻度发作后脑血管壁细胞表达进行性下降。 小鼠脑损伤(r-mTBI)。此外，来自r-mTBI动物的分离的脑血管内化和 过程中的牛磺酸比未受伤的动物。据我们所知，这是第一次观察到微扰的研究 脑创伤背景下的壁细胞表达和tau蛋白的加工。重要的是，在壁画细胞旁边 在我们的小鼠r-mTBI模型中，我们观察到总tau、磷酸化tau和 大脑中的寡聚体tau物种。此外，我们还表明，大脑中tau的清除减少了 与野生型小鼠相比，转基因壁细胞耗尽的动物。我们认为脑血管壁画 细胞是处理和清除细胞外脑液中tau的途径，这种干扰 这些细胞中的一部分会导致tau病理和神经变性。该项目的目标是确定 脑血管壁细胞在脑外伤后tau病理中的作用。这样做的具体目的是 建议：1)检查壁细胞耗竭动物和人类脑外伤的壁细胞状态和tau病理。 大脑，2)评估壁细胞在tau降解和消除中的作用以及r-mTBI对这些作用的影响 3)确定壁细胞在血管旁(淋巴)tau清除和血管周围的作用 R-mTBI后脑组织中的tau引流。为了确定脑外伤后的壁细胞状态，tau摄取和 各种壁细胞标记物将在分离的壁细胞耗尽动物的脑血管中进行检测 和人的脑损伤标本。为了了解壁细胞对tau倾向的影响，tau 将在r-mTBI动物的分离脑血管系统中评估降解情况，并从 大脑将在壁细胞耗尽的动物和r-mTBI小鼠身上进行检查。最后，要了解 壁细胞对r-TBI后脑液中细胞外tau运动的影响，我们将检查两种血管旁 (淋巴)tau清除和血管周围tau引流从脑壁细胞耗竭动物和r- MTBI小鼠。建议的研究将加深我们对tau加工和消除的了解。 并确定脑血管壁细胞在tau病理中的作用 脑外伤后神经退行性变表型。