Connecting Alzheimer's Disease to Traumatic Synaptic Neurodegeneration

将阿尔茨海默病与创伤性突触神经变性联系起来

• 批准号: 10613410
• 负责人: TERRANCE T KUMMER
• 金额: $ 43.93万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613410
• 关键词: Acute Brain Injuries; Admixture; Age; Aging; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Amyloidosis; Animal Model; Area; Atrophic; Automobile Driving; Biochemical Process; Biological; Brain; Brain Diseases; Brain Injuries; Brain region; Cause of Death; Chemosensitization; Chronic; Clinical; Cognition; Cognitive; Complement; Complement Activation; Complex; Data; Dementia; Diffuse; Disease; Elements; Emotional; Environmental Risk Factor; Epidemiology; Epigenetic Process; Evaluation; Event; Excitatory Synapse; Face; Functional disorder; Genetic; Half-Life; Head; Health; Human; Image; Image Analysis; Imaging Device; Impaired cognition; Individual; Injury; Innate Immune System; Intervention; Link; Longevity; Measures; Mediating; Mediator; Modeling; Monitor; Mus; Nanostructures; Nerve Degeneration; Neurologic; Neurons; Neuropil; Neuropsychology; Outcome; Pathologic; Pathology; Pattern; Phase; Play; Process; Public Health; Reproducibility; Role; Senile Plaques; Structure; Symptoms; Synapses; Tauopathies; Therapeutic; Time; Trauma; Traumatic Brain Injury; advanced disease; aged; axon injury; behavioral outcome; chronic traumatic encephalopathy; clinical translation; clinically relevant; complement pathway; complement system; demented; disability; effective therapy; empowerment; gray matter; improved; innovation; middle age; mild traumatic brain injury; mouse model; neural; neural circuit; neurobehavioral; neuroinflammation; neuron loss; neuropathology; novel; pharmacologic; pre-clinical; prevent; resilience; social; superresolution imaging; tau Proteins; tau aggregation; therapeutic target; tool; white matter; young adult

Alzheimer’s disease (AD) is a global public health crisis with unknown triggers and no disease modifying therapies. Effective treatments likely must be initiated in the early phases of biological disease, well before brain reserves of the neural substrates of cognition are depleted leading to overt clinical symptoms. These ‘preclinical’ periods and their triggering events, therefore, are highly significant areas of study. Traumatic brain injury (TBI), the leading cause of death and disability in younger individuals (under age 45) worldwide, is also the best-established epigenetic risk factor for AD. Once thought to be a monophasic injury, TBI is now known to initiate a chronic neuroinflammatory and neurodegenerative process that leads through unknown pathological mediators to dementing illnesses including AD, ADRDs, and chronic traumatic encephalopathy (CTE). Synapse loss is a common, early finding in AD, and the strongest pathological correlate of AD-induced dementia—even stronger than amyloid plaques or tau neurofibrillary tangles. Synaptic injury is also implicated in TBI in humans and in animal models. Synapses are challenging to study due to their extremely small size and admixture with 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 Nanostructure) to enable routine monitoring of synaptic health in animal models and in humans. Our preliminary data demonstrate that delayed cortical synapse loss occurs after diffuse, closed head, mild TBI in a mouse model, suggesting that synaptic neurodegeneration may lead to neurological disability following TBI and sensitize the brain to subsequent AD-related synapse loss, hastening the onset of dementia. We will characterize synaptic neurodegeneration resulting from mild TBI over the lifespan, and determine its ability to predict neuropsychological and behavioral outcomes. We will then assess complement activation—a component of the innate immune system that drives synapse loss in AD and is maladaptively activated after mild TBI— as a mechanism of synaptic neurodegeneration. We will determine whether targeting the complement pathway can improve synaptic health and improve behavioral outcomes using genetic and clinically-translatable pharmacological interventions. Finally, we will assess the impact of mild TBI on synaptic neurodegeneration related to amyloidosis and tauopathy, classic AD-related neuropathological and biochemical processes. We will determine whether complement inhibition can prevent TBI-induced potentiation of neurodegeneration in mouse models of these processes. These studies are expected to reveal intervenable links between early brain injury and long-term neurodegeneration relevant to the individuals at greater risk of AD and related brain disorders due to an earlier TBI. They will also further establish innovative synaptic imaging tools (SEQUIN) that will empower routine synaptic analysis in this and related fields.

阿尔茨海默病（AD）是一种全球性的公共卫生危机，其诱因未知，且无法改变疾病 治疗有效的治疗可能必须在生物疾病的早期阶段开始， 认知的神经基质的脑储备被耗尽，导致明显的临床症状。这些 因此，“临床前”时期及其触发事件是非常重要的研究领域。创伤性脑 创伤（TBI）是全球年轻人（45岁以下）死亡和残疾的主要原因， AD的表观遗传风险因素。TBI曾被认为是一种双相损伤， 引发慢性神经炎症和神经退行性病变 痴呆疾病（包括AD、ADRD和慢性创伤性脑病）的病理介质 （CTE）。突触丢失是AD中常见的早期发现，并且是AD诱导的突触丢失的最强病理相关性。 痴呆症-甚至比淀粉样斑块或tau神经元缠结更严重。突触损伤也与 在人类和动物模型中的TBI。突触的研究具有挑战性，因为它们的尺寸非常小， 与哺乳动物神经细胞异常复杂的亚细胞环境混合。我们开发了一个 创新的、可广泛访问的超分辨率成像和图像分析平台SEQUIN（Synaptic 通过成像纳米结构的评估和定量），以使得能够常规监测突触健康。 动物模型和人类。我们的初步数据表明， 在小鼠模型中弥漫性，闭合头部，轻度TBI后，表明突触神经变性可能导致 TBI后的神经功能障碍，并使大脑对随后的AD相关突触丢失敏感， 痴呆症的发病我们将描述轻度TBI引起的突触神经变性， 寿命，并确定其预测神经心理和行为结果的能力。我们将评估 补体激活-先天免疫系统的一种成分，其驱动AD中的突触丧失， 在轻度TBI后不适应地激活-作为突触神经变性的机制。我们将确定 靶向补体通路是否可以改善突触健康并改善行为结果 使用遗传学和临床上可翻译的药理学干预。最后，我们将评估 轻度TBI对与淀粉样变性和tau蛋白病相关的突触神经变性，经典AD相关 神经病理学和生物化学过程。我们将确定补体抑制是否能阻止 在这些过程的小鼠模型中TBI诱导的神经变性增强。这些研究 预计将揭示早期脑损伤和长期神经退行性变之间的可干预联系， 由于早期TBI，AD和相关脑部疾病的风险更大。他们还将进一步 建立创新的突触成像工具（SEQUIN），这将使常规突触分析， 相关领域