Traumatic axonopathy and Alzheimer tau propagation

项目总结 在这个应用中，我们探索轴突损伤在中枢神经系统蛋白质聚集体传播中的作用。 关于已知的创伤性脑损伤与神经退行性疾病之间的联系。重点放在这里 在微管相关蛋白tau上，它经历了一些修饰，然后聚集在一起 在所谓的神经退行性疾病的标志性沉积中，包括阿尔茨海默病 (AD)和慢性创伤性脑病(CTE)。具体地说，我们提出轴突病理和节段性神经病 相互作用和中枢神经系统轴突的完整性是影响tau增殖的关键独立因素 相互连接的大脑区域的过度磷酸化或聚集。我们的建议是以试点数据为基础的 证实了其他研究小组的发现，即我们可以在前脑和一些脑干产生广泛的直立性脑病 在大脑皮层和海马区注射从阿尔茨海默病脑中提取的纤维状tau(AD-tau)后的回路。更多 重要的是，我们最近确定了无菌阿尔法和热/Armadillo基序的作用，该基序包含1 (Sarm1)，沃勒氏轴突变性的主要触发因素，是创伤性轴突的关键指示信号 中枢神经系统的分解和识别可能干扰Sarm1相关的中枢神经系统穿透小分子 发信号。我们的提案有两个具体目标。在目标1中，我们探索创伤性轴索损伤， 通过降解轴突结构，加速/扩大通过在小鼠脑内种植AD-1而引起的紧张症。 在宿主大脑回路中形成病理性(过度磷酸化/聚集)的tau信号。在这里，我们建议 弥漫性颅脑损伤中心液体撞击模型所致轴索损伤将促进tau的传播 用从阿尔茨海默病患者脑中提取的tau种子接种于小鼠的海马区和大脑皮层的病理学。在AIM 2我们探讨了轴突变性信号sarm1在tau病理系统传播中的作用。 远离最初的AD-tau接种部位和相关的神经炎症。在这里，我们建议通过 删除Sarm1，从而在与目标1相同的弥漫性脑损伤模型中保护轴突，我们可能会改善严重程度 以及基线或损伤加重的紧张症和相关的神经炎症，最终， 抑制神经变性/细胞死亡。为了达到前面的目标，我们使用了解剖学和 基因工具包括Sarm1基因敲除小鼠和高分辨率神经病理学，其中包括大脑 清晰度、屏蔽度和电子显微镜等清除方法。一旦我们将Sarm1确立为 一个相关的分子靶点，那么我们将能够更准确地证实这些发现 使用我们实验室提供的CRISPR方法和干扰Sarm1的小分子进行基因编辑 发信号。总之，通过探索Sarm1在易于聚集或聚集的tau的传播中的作用， 我们寻求一种新的方法来理解包括AD在内的神经退行性疾病的机制 和CTE。因为Sarm1相关的信号可能很快就会被小分子解决，我们也发现 具有巨大治疗潜力的分子靶点。

PROJECT SUMMARY In this application we explore the role of axonal injury in the propagation of protein aggregates in the CNS, based on the known association between traumatic brain injury (TBI) and neurodegenerative disease. Emphasis here is on the microtubule-associated protein tau, which undergoes a number of modifications and then aggregates in hallmark deposits in the so-called tauopathies, neurodegenerative diseases that include Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). Specifically, we propose that axonal pathology and tauopathy interact and that the integrity of CNS axons is a key independent factor influencing propagation of tau hyperphosphorylation or aggregation across interconnected brain regions. Our proposal is founded on pilot data confirming findings from other groups that we can generate extensive tauopathy in forebrain and some brainstem circuits after injections of fibrillar tau extracted from AD brains (AD-tau) in cortex and hippocampus. More importantly, we have recently established the role of sterile alpha and HEAT/Armadillo motif containing 1 (SARM1), the main trigger of Wallerian axonal degeneration, as a key instructive signal for traumatic axonal breakdown in the CNS and identified small CNS-penetrant molecules that may interfere with SARM1-related signaling. Our proposal is organized in two specific aims. In Aim 1 we explore whether traumatic axonal injury, by degrading axon structure, accelerates/expands the tauopathy induced by seeding the mouse brain with AD- tau to form pathological (hyperphosphorylated/aggregated) tau signatures in host brain circuits. Here we propose that axonal injury caused by the central fluid percussion model of diffuse TBI will facilitate the propagation of tau pathology in mice inoculated in the hippocampus and neocortex with tau seeds extracted from AD brains. In Aim 2 we explore the role of the axonal degeneration signal SARM1 in the systems propagation of tau pathology away from the initial AD-tau inoculation sites and in the related neuroinflammation. Here we propose that by deleting SARM1, thus protecting axons in the same diffuse TBI model as Aim 1, we may ameliorate the severity and spread of baseline or injury-accentuated tauopathy and the related neuroinflammation and, eventually, suppress neurodegeneration/cell death. To achieve the previous aims, we use a complement of anatomical and genetic tools including SARM1 knockout mice and high-resolution neuropathology including, among else, brain clearing methodologies such as CLARITY and SHIELD and electron microscopy. Once we establish SARM1 as a relevant molecular target in tauopathy, then we will be in position to confirm these findings with more precise gene editing using CRISPR methodologies available in our lab and small molecules that interfere with SARM1 signaling. In concert, by exploring the role of SARM1 in the propagation of aggregation-prone or aggregated tau, we pursue a new approach in understanding the mechanisms of neurodegenerative tauopathies, including AD and CTE. Because SARM1-related signaling may be soon tackled with small molecules, we also identify molecular targets with substantial therapeutic potential.