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: 10366645
• 负责人: TERRANCE T KUMMER
• 金额: $ 38.17万
• 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/10366645
• 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; Contusions; 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; Interneurons; Intervention; Lead; Link; Longevity; Measures; Mediating; Mediator of activation protein; Modeling; Monitor; Mus; Nanostructures; Nerve Degeneration; Neurologic; Neuropil; Neuropsychology; Outcome; Pathologic; Pathology; Pattern; Pharmacology; Phase; Play; Process; Public Health; Reproducibility; Resolution; Role; Senile Plaques; Structure; Symptoms; Synapses; Tauopathies; Therapeutic; Time; Trauma; Traumatic Brain Injury; advanced disease; axon injury; base; behavioral outcome; chronic traumatic encephalopathy; clinically relevant; clinically translatable; complement pathway; complement system; disability; effective therapy; gray matter; improved; innovation; middle age; mild traumatic brain injury; mouse model; neural circuit; neurobehavioral; neuroinflammation; neuron loss; novel; pre-clinical; prevent; relating to nervous system; resilience; social; 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.

阿尔茨海默氏病（AD）是一场全球公共卫生危机，触发不明，没有改变疾病 疗法。有效的治疗可能必须在生物疾病的早期阶段开始 认知神经底物的脑部储量耗尽，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。创伤性大脑 伤害（TBI）是全球年轻人（45岁）的死亡和残疾的主要原因，也是 AD的最佳表观遗传风险因素。曾经被认为是单型损伤，TBI现在已知 启动慢性神经炎症和神经退行性过程，该过程通过未知 病理介导者，包括AD，ADRD和慢性创伤性脑病在内的痴呆疾病 （CTE）。突触损失是AD中常见的早期发现，并且AD诱导的强病理性相关 痴呆症 - 比淀粉样蛋白斑块或tau神经纤维缠结更强。突触损伤也暗示 在人类和动物模型中的TBI中。由于突触的尺寸很小，突触挑战了研究 与哺乳动物神经胶质的非常复杂的亚细胞环境混合。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 通过成像纳米结构进行评估和量化）以常规监测突触健康 动物模型和人类。我们的初步数据表明，延迟的皮质突触损失发生 散射后，闭合头，小鼠模型中的轻度TBI，表明合成神经变性可能会导致 TBI后神经疾病，并感知大脑随后与广告相关的突触丧失，加速 痴呆症的发作。我们将表征由轻度TBI在 生命周期，并确定其预测神经心理学和行为结果的能力。然后我们将评估 补体激活 - 先天免疫系统的组成部分，该系统驱动AD中的突触损失，IS 轻度TBI后不良激活 - 作为突触神经退行性的机制。我们将确定 针对补体途径是否可以改善突触健康并改善行为结果 使用遗传和临床转化的药物干预措施。最后，我们将评估 轻度TBI关于与淀粉样蛋白病和经典广告相关的合成神经退行性变性 神经病理学和生化过程。我们将确定完成抑制是否可以防止 TBI诱导的这些过程小鼠模型中神经退行性的增强。这些研究是 预计将揭示早期脑损伤与长期神经变性之间的间歇性联系 由于较早的TBI，患有AD和相关脑部疾病的风险更大。他们也将进一步 建立创新的突触成像工具（亮片），该工具将在此和 相关字段。