Traumatic axonopathy and Alzheimer tau propagation

创伤性轴突病和阿尔茨海默氏tau蛋白增殖

• 批准号: 10590970
• 负责人: VASSILIS E. KOLIATSOS
• 金额: $ 45.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590970
• 关键词: Acceleration; Alzheimer' s Disease; Alzheimer' s disease brain; Anatomy; Area; Axon; Brain; Brain Stem; Brain region; CRISPR/Cas technology; Cell Death; Chronic; Complement; Data; Deposition; Diffuse; Diffuse Axonal Injury; Disease Progression; Electron Microscopy; Enzymes; Event; Family Dasypodidae; Frontotemporal Lobar Degenerations; Genes; Genetic; Goals; Hippocampus; Inflammatory Response; Injections; Injury; Knock-out; Knockout Mice; Liquid substance; MAPT gene; Methodology; Microglia; Modeling; Modification; Molecular; Molecular Target; Mus; Neocortex; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathologic; Pathology; Percussion; Positioning Attribute; Process; Prosencephalon; Resolution; Role; Severities; Signal Transduction; Site; Sterility; Structure; Synapses; System; Tauopathies; Therapeutic; Traumatic Brain Injury; Wallerian Degeneration; Wild Type Mouse; Work; axon injury; axonal degeneration; axonopathy; chronic traumatic encephalopathy; hyperphosphorylated tau; injured; neocortical; neuroinflammation; neuron loss; neuronal cell body; neuropathology; neurotransmission; novel; novel strategies; prevent; protein aggregation; small molecule; tau Proteins; tau aggregation; tau mutation; tool; trafficking

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.

项目摘要 在本申请中，我们探索轴突损伤在CNS中蛋白质聚集体增殖中的作用， 创伤性脑损伤（TBI）和神经退行性疾病之间的已知关联。这里强调 是在微管相关蛋白tau上，它经历了许多修饰，然后聚集 在所谓的tau蛋白病（包括阿尔茨海默病在内的神经退行性疾病）的标志性沉积中 (AD)慢性创伤性脑病（CTE）。具体来说，我们认为轴突病理和tau蛋白病 相互作用，CNS轴突的完整性是影响tau传播的关键独立因素 过度磷酸化或聚集在相互连接的大脑区域。我们的建议是以试验数据为基础的 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中产生广泛的tau蛋白病变 在皮质和海马中注射从AD脑提取的纤维状tau（AD-tau）后的回路。更 重要的是，我们最近已经确定了不育α和HEAT/Armadillo基序的作用， SARM 1是Wallerian轴突变性的主要触发因子，作为创伤性轴突变性的关键指导信号， CNS中的分解，并确定了可能干扰SARM 1相关 信号我们的建议有两个具体目标。在目标1中，我们探讨创伤性轴索损伤， 通过降解轴突结构，加速/扩大了通过用AD接种小鼠脑诱导的tau蛋白病， 在宿主脑回路中形成病理性（过度磷酸化/聚集的）tau标记。在这里我们建议 由弥漫性TBI的中央流体冲击模型引起的轴突损伤将促进tau蛋白的传播 在海马和新皮质中接种从AD脑提取的tau种子的小鼠中的病理学。在Aim中 2我们探索了轴突变性信号SARM 1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。在此，我们建议， 删除SARM 1，从而在与Aim 1相同的弥漫性TBI模型中保护轴突， 以及基线或损伤加重的tau蛋白病和相关神经炎症的扩散，最终， 抑制神经变性/细胞死亡。为了实现上述目标，我们使用了解剖学和 遗传工具，包括SARM 1敲除小鼠和高分辨率神经病理学，包括脑 清除方法，如荧光和盾牌和电子显微镜。一旦我们确定SARM 1为 tau蛋白病的相关分子靶点，那么我们将能够更精确地证实这些发现。 基因编辑使用CRISPR方法在我们的实验室和小分子干扰SARM 1 信号一致地，通过探索SARM 1在聚集倾向或聚集的tau蛋白的传播中的作用， 我们寻求一种新的方法来理解神经退行性tau蛋白病的机制，包括AD 和CTE。由于SARM 1相关的信号可能很快就会被小分子所解决，我们还确定了 具有巨大治疗潜力的分子靶点。