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 (TBI) 是 45 岁以下成年人死亡和残疾的主要原因，影响 近 20% 的退伍军人曾经被认为是一种单相损伤，但现在已知会引发一种损伤。 惰性神经退行性过程会大大增加患阿尔茨海默氏症和其他形式的疾病的风险 老年退伍军人的痴呆症由 TBI 引起的所有残疾都源于其神经功能的破坏。 TBI 中断这些网络并引起进一步神经退行性病变的机制。 尽管在白质中观察到的损伤位点之外的损伤位点尚未得到充分定义， 在人类和动物模型中，人们越来越认识到 TBI 后的突触损伤。 导致突触的病理性分子、结构和功能变化，或突触的直接损失。 丢失也是阿尔茨海默病 (AD) 中常见的早期发现，它是最强的病理相关性 AD 引起的痴呆的影响甚至比淀粉样斑块或 tau 神经炎症通路更强。 在动物模型和人类中，TBI 后会长期激活，并在 介导 AD 中的突触损失 更好地了解 TBI 中的突触损伤及其神经炎症。 因此，中介体可以提供缺失的且可能中断的结构-机械连接 然而，由于突触的尺寸极小，因此研究它们非常具有挑战性。 并混合在哺乳动物神经纤维极其复杂的亚细胞环境中。 创新的、广泛使用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），以实现对突触健康状况的常规监测 我们的初步数据表明，动物模型和人类的突触丢失是一个显着特征。 在军事相关小鼠模型中发现弥漫性、闭合性头部 TBI，并表明补体的抑制 通路（先天免疫系统的一部分）可防止创伤性突触丧失并改善 TBI 后的功能。 这些发现表明，神经炎症性突触损伤导致急性神经功能障碍 弥漫性 TBI 并使大脑对随后的神经退行性变化敏感，加速发生 我们建议首先（目标 1）描述弥漫性 TBI 引起的区域突触损失和 以不可能的规模确定其神经心理学和行为相关性，以实现 pre-SEQUIN。 然后（目标 2）确定补体途径在介导创伤性突触损失中的作用，并且 确定该通路的遗传和/或药理学靶向是否可以挽救突触终点 最后，我们将（目标 3）确定 TBI 是否以及如何增强突触。 这些研究表明，AD 患者在晚年会因淀粉样蛋白和 tau 蛋白相关的神经变性而丧失。 预计将揭示 TBI 后与认知相关的新的、可药物化的回路损伤机制 此外，他们还会在返回现役军人、警卫和预备役人员时出现情绪障碍。 建立创新工具（SEQUIN）来了解对退伍军人具有独特意义的情况， 并确定 AD 与其最确定的表观遗传风险因素（大脑）之间的可干预机制联系 创伤。