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: 10117764
• 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/10117764
• 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 Structure; 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; Structure; 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.

创伤性脑损伤是45岁以下成年人死亡和残疾的主要原因，影响 ∼20%的退伍军人来自最近的战争。曾经被认为是单相性损伤，现在已知脑外伤会引发 惰性神经退行性变过程，大大增加阿尔茨海默氏症和其他形式的 老年退伍军人的痴呆症。颅脑损伤导致的所有残疾都源于其对功能神经的破坏 网络。脑损伤阻断这些网络并建立进一步的神经退行性变的机制 尽管白质中观察到的损伤部位以外的损伤部位没有得到充分的定义，但网络崩溃的定义并不充分 越来越受到人们的认可。已经在人类和动物模型中发现了脑损伤后的突触损伤， 导致突触的病理性分子、结构和功能改变，或其坦率的丧失。突触 丢失也是阿尔茨海默病(AD)的一种常见的早期发现，在那里它是最强的病理相关性 阿尔茨海默病引起的痴呆症--甚至比淀粉样斑块或tau缠结还要强烈。神经炎性通路 在动物模型和人类脑损伤后被长期激活，并在 在AD中调节突触丢失。加深对颅脑损伤后突触损伤及其神经炎性的认识 因此，调解人可以补充一种缺失的、可能会中断的结构性-机械性联系 在这两种情况之间。然而，突触的研究非常具有挑战性，因为它们的尺寸非常小 以及哺乳动物神经纤维异常复杂的亚细胞环境中的混合物。我们开发了一种 创新的、可广泛访问的超分辨率成像和图像分析平台，称为Sequin(Synaptic 通过纳米结构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，突触丢失是老年痴呆症的一个显著特征 在军事相关的小鼠模型中弥漫性、闭合性头部脑损伤，并表明补体受到抑制 通路(先天免疫系统的一部分)可防止创伤性突触丢失，并改善脑损伤后的功能。 这些发现表明，神经炎性突触损伤导致急性神经功能障碍 弥漫性脑损伤并使大脑对随后的神经退行性变化敏感，加速脑损伤的发生 痴呆症。我们建议首先(目标1)表征弥漫性脑损伤所致的区域突触丢失和 确定其神经心理和行为的相关性，达到无法达到亮片前的水平。我们 然后(目标2)将确定补体途径在调节创伤性突触丢失中的作用，以及 确定该通路的遗传和/或药物靶向是否可以挽救突触终点 并改善功能结果。最后，我们将(目标3)确定脑外伤是否以及如何增强突触 阿尔茨海默病的典型特征是淀粉样蛋白和tau蛋白相关的神经变性，导致晚年生活中的损失。这些研究 有望揭示与认知有关的脑外伤后电路损伤的新的、可用药的机制 以及返回现役军人、警卫和预备役人员时的精神残疾。他们还将进一步 建立创新工具(亮片)，以了解对退伍军人具有独特意义的状况， 并确定AD与其最可靠的表观遗传风险因素--大脑之间的可干预机制联系 精神创伤。