Imaging Synaptic Injury in TBI using SEQUIN

使用 SEQUIN 对 TBI 中的突触损伤进行成像

• 批准号: 10347182
• 负责人: TERRANCE T KUMMER
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10347182
• 关键词: APP-PS1; Acute; Admixture; Adolescent and Young Adult; Adult; Affect; Age; Aging; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease risk; Americas; Amyloid; Amyloidosis; Animal Model; Atrophic; Automobile Driving; Behavior monitoring; Behavioral; Brain; Brain region; Cause of Death; Chronic; Cognitive; Complement; Complex; Data; Dementia; Diffuse; Elements; Emotional; Environmental Risk Factor; Epigenetic Process; Evaluation; Excitatory Synapse; Fright; Functional disorder; Genetic; Head; Health; Human; Human Resources; Image; Image Analysis; Immune system; Impaired cognition; Indolent; Inflammatory; Injury; Innate Immune System; Interneurons; Interruption; Life; Link; Measures; Mediating; Mediator of activation protein; Military Personnel; Modeling; Molecular; Monitor; Nanostructures; Nerve Degeneration; Neurofibrillary Tangles; Neurologic; Neuropil; Neuropsychology; Outcome; Pathologic; Pathology; Pathway interactions; Pattern; Pharmacology; Play; Process; Public Health; Resolution; Risk Factors; Role; Senile Plaques; Synapses; TBI treatment; Tauopathies; Time; Trauma; Traumatic Brain Injury; Veterans; War; active duty; advanced disease; analysis pipeline; axon injury; base; complement pathway; cost; disability; falls; functional outcomes; gray matter; immune activation; improved; improved functioning; improved outcome; injured; innovation; loss of function; middle age; mouse model; neural circuit; neural network; neurobehavioral; neuroinflammation; neuron loss; novel; prevent; resilience; response; service member; social; stem; tau Proteins; tau aggregation; therapeutic target; tool; white matter; young adult

Traumatic brain injury (TBI) is the leading cause of death and disability in adults under the age of 45, affecting ∼20% of veterans from recent wars. Once thought to be a monophasic injury, TBI is now known to trigger an indolent neurodegenerative process that substantially increases the risk of Alzheimer’s and other forms of dementia for older veterans. All disability resulting from TBI stems from its disruption of functional neural networks. The mechanisms by which TBI interrupts these networks and sets up further neurodegenerative network breakdown are inadequately defined, though injury loci beyond those observed in white matter are increasingly recognized. Synaptic injury has been identified following TBI in humans and in animal models, resulting in pathological molecular, structural, and functional changes to synapses, or their frank loss. Synapse loss is also a common, early finding in Alzheimer’s disease (AD) where it is the strongest pathological correlate of AD-induced dementia—even stronger than amyloid plaques or tau tangles. Neuroinflammatory pathways are activated in a prolonged fashion after TBI in animal models and in humans, and play a central role in mediating synapse loss in AD. A better understanding of synaptic injury in TBI, and its neuroinflammatory mediators, therefore, could supply a missing and potentially interruptible structural-mechanistic connection between these conditions. Synapses, however, are very challenging to study due to their extremely small size and admixture within the extraordinarily complex subcellular milieu of mammalian neuropil. We developed an innovative, widely accessible super-resolution imaging and image analysis platform called SEQUIN (Synaptic Evaluation and QUantification by Imaging of Nanostructure) to enable routine monitoring of synaptic health in animal models and in humans. Our preliminary data demonstrate that synapse loss is a prominent feature of diffuse, closed head TBI in a militarily-relevant mouse model, and indicate that inhibition of the complement pathway (part of the innate immune system) prevents traumatic synapse loss and improves function after TBI. These findings suggest that neuroinflammatory synaptic injury leads to acute neurological disability following diffuse TBI and sensitizes the brain to subsequent neurodegenerative changes, hastening the onset of dementia. We propose to first (Aim 1) characterize regional synapse loss resulting from diffuse TBI and determine its neuropsychological and behavioral correlates at a scale impossible to achieve pre-SEQUIN. We will then (Aim 2) determine the role of the complement pathway in mediating traumatic synapse loss, and determine whether genetic and/or pharmacological targeting of this pathway can rescue synaptic endpoints and improve functional outcomes. Lastly, we will (Aim 3) determine whether and how TBI potentiates synapse loss later in life in response to the amyloid- and tau-related neurodegeneration that typifies AD. These studies are expected to reveal novel, druggable mechanisms of circuit injury after TBI that are connected to cognitive and emotional disability in returning active military, guard, and reserve personnel. They will furthermore establish innovative tools (SEQUIN) for the understanding of conditions with unique significance for veterans, and identify an intervenable mechanistic link between AD and its best-established epigenetic risk factor, brain trauma.

创伤性脑损伤（TBI）是45岁以下成人死亡和残疾的主要原因，影响 最近战争中约有20％的退伍军人。曾经被认为是单个损伤，现在已知TBI触发 懒惰的神经退行性过程大大增加了阿尔茨海默氏症和其他形式的风险 老年退伍军人的痴呆症。 TBI植物造成的所有残疾，其功能中性的破坏 网络。 TBI中断这些网络并建立进一步的神经退行性的机制 网络分解的定义不足，尽管在白质中观察到的伤害基因座超出了伤害基因座 越来越认可。在人类和动物模型中TBI后，已经发现了突触损伤， 导致突触的病理分子，结构和功能变化或坦率的损失。突触 在阿尔茨海默氏病（AD）中，损失也很常见，它是强大的病理相关性 广告诱导的痴呆症 - 甚至比淀粉样蛋白斑块或tau缠结强。神经炎症途径 在动物模型和人类中以TBI之后以长时间的方式激活，并在 介导AD中的突触损失。更好地了解TBI突触损伤及其神经炎症性 因此，调解员可以提供缺失且可能中断的结构机械连接 在这些条件之间。但是，由于突触的尺寸极小，突触非常挑战 并在哺乳动物神经胶质的非常复杂的亚细胞环境中混合。我们开发了一个 创新的，广泛访问的超分辨率成像和图像分析平台称为亮片（突触 通过对纳米结构的成像进行评估和量化），以实现对突触健康的常规监测 动物模型和人类。我们的初步数据表明，突触损失是 与军事相关的鼠标模型中的弥漫性，闭合头TBI，并表明抑制完成 途径（先天免疫系统的一部分）可防止创伤性突触损失并改善TBI后的功能。 这些发现表明，神经炎性合成损伤导致急性神经系统残疾 扩散TBI并将大脑感知到随后的神经退行性变化，从而加快了 失智。我们建议首先（AIM 1）表征弥漫性TBI和 确定其神经寄生和行为的相关性，无法实现前续。我们 然后（AIM 2）确定完成途径在介导创伤突触损失的作用，并且 确定该途径的遗传和/或药理靶向是否可以挽救突触终点 并改善功能结果。最后，我们将（AIM 3）确定TBI是否以及如何增强突触 响应淀粉样蛋白和TAU相关的神经退行性的响应，其损失为AD。这些研究 期望揭示与认知有关 以及返回活跃的军事，警卫和保留人员的情绪残疾。他们将进一步 建立创新工具（亮片），以理解对退伍军人的独特意义的条件， 并确定AD及其最佳表观遗传危险因素之间的可间歇机械联系，大脑 创伤。