Connecting Alzheimer's Disease to Traumatic Synaptic Neurodegeneration

阿尔茨海默病(AD)是一种诱因不明、无疾病修饰的全球性公共卫生危机 治疗。有效的治疗可能必须在生物性疾病的早期阶段开始，很久以前 认知神经基础的大脑储备耗尽，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 伤害(TBI)是全世界年轻人(45岁以下)死亡和残疾的主要原因，也是 阿尔茨海默病的最佳表观遗传风险因素。曾经被认为是单相性损伤，现在被认为是 启动慢性神经炎性和神经退行性变的过程 痴呆疾病的病理介质，包括AD、ADRDS和慢性创伤性脑病 (CTE)。突触丢失是阿尔茨海默病常见的早期发现，也是阿尔茨海默病最强的病理相关性 痴呆症--甚至比淀粉样斑块或tau神经原纤维缠结更严重。突触损伤也牵涉其中 在人类和动物模型的脑损伤中。突触的研究具有挑战性，因为它们的体积非常小，而且 与哺乳动物神经纤维的异常复杂的亚细胞环境混合。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 通过成像纳米结构进行评估和量化)，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，延迟性皮质突触丢失 在弥漫性、闭合性头部、轻度脑损伤后的小鼠模型中，提示突触神经退行性变可能导致 颅脑损伤后的神经功能障碍并使大脑对随后与AD相关的突触丢失、加速敏感 痴呆症的发作。我们将描述由轻度脑损伤引起的突触神经退行性变。 寿命，并确定其预测神经心理和行为结果的能力。然后我们将评估 补体激活-先天免疫系统的一个组成部分，导致AD和 轻度脑外伤后适应性不良激活--作为突触神经变性的一种机制。我们将决定 靶向补体途径是否可以改善突触健康和改善行为结果 使用遗传和临床可翻译的药理学干预。最后，我们将评估 轻度脑损伤对典型AD相关的淀粉样变性和肌萎缩侧索硬化症相关突触神经变性的影响 神经病理和生化过程。我们将确定抑制补体是否可以预防 在这些过程的小鼠模型中，脑损伤诱导神经退行性变的增强。这些研究是 有望揭示早期脑损伤和长期神经退行性变之间的可干预联系 由于较早的脑外伤而导致AD和相关脑部疾病风险较高的个体。他们还将进一步 建立创新的突触成像工具(亮片)，使常规突触分析成为可能 相关字段。

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.