The Importance of Abnormal Inflammasome Activation as a Risk Factor between Traumatic Brain Injury and Alzheimer’s Disease

异常炎症体激活作为创伤性脑损伤和阿尔茨海默病之间危险因素的重要性

• 批准号: 10700483
• 负责人: JUAN Pablo DE RIVERO VACCARI
• 金额: $ 167.13万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700483
• 关键词: Importance; Abnormal; Inflammasome; Activation; Risk

Traumatic brain injury (TBI) is a risk factor for the development of Alzheimer’s disease (AD) and Alzheimer’s Disease Related Dementias (AD/ADRD). Although much work has been done in evaluating pathophysiological mechanisms of TBI and AD, the relationships between these two conditions is not completely understood. The role of inflammation in the pathophysiology of TBI and neurodegenerative diseases has been reported in the experimental and clinical literature. Accordingly, TBI and neurodegenerative diseases share many pathological and immunological hallmarks that indicate potential relationships that are critical as therapeutic strategies are developed. Recently, our laboratories, as well as others, have helped clarify the importance of abnormal inflammasome signaling in the pathogenesis of TBI and in the aging brain. These findings indicate that an innate inflammatory response plays a critical role in multiple pathophysiological events in neurodegenerative diseases such as AD. New evidence for the release of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)-specks from microglial cells has provided further evidence for inflammasome activation in AD. Importantly, ASC- specks with prion-like properties contribute to the deleterious effects of the innate immune response mediated by the inflammasome. The overall goal of the proposed studies is to determine mechanisms underlying TBI-induced inflammasome activation as a risk factor for AD and to evaluate targeted therapeutic approaches to improve outcomes in this patient population. Our central hypothesis is that inflammasome activation in AD augments TBI-induced inflammation by a mechanism, mediated in part by extracellular vesicle (EV) containing inflammasome proteins and ASC-speck accumulation, that contributes to worsened AD pathology and memory impairments. To test this hypothesis the following aims will be pursued: Aim 1) To determine the temporal profile and the mechanisms underlying the detrimental effects of TBI on inflammasome activation in AD mice; Aim 2) To investigate the role of abnormal inflammasome activation and ASC-specks in microglia as an underlying mechanism for the deleterious effects of TBI in AD mice and Aim 3) To determine the therapeutic effects of inflammasome inhibition and ASC-speck formation on histopathological and behavioral outcomes after TBI in WT and AD-transgenic mice. The proposed studies will provide new information on how specific genetic risk factors for AD may heighten TBI- induced neurodegenerative processes and lead to AD-related pathological and progressive cognitive decline. Moreover, these studies will advance current inflammasome research into the AD/ADRD field to elucidate novel mechanisms underlying how TBI contributes to the onset of neurodegenerative disorders, and provide a new direction for evaluating therapeutic interventions targeting abnormal inflammasome activation after TBI in AD-transgenic mice for potential translation to the clinic.

脑外伤（TBI）是阿尔茨海默病（AD）和阿尔茨海默病发展的危险因素 疾病相关性痴呆（AD/ADRD）。尽管在评估方面已经做了很多工作， TBI和AD的病理生理机制，这两种情况之间的关系不是 完全理解炎症在TBI病理生理学和神经退行性变中的作用 在实验和临床文献中已经报道了这种疾病。因此，TBI和 神经退行性疾病共有许多病理学和免疫学特征， 这些关系对于制定治疗策略至关重要。最近，我们的实验室，以及 其他人的研究有助于阐明异常炎性体信号在TBI发病机制中的重要性 和老化的大脑中。这些发现表明，先天性炎症反应在 神经退行性疾病如AD中的多种病理生理学事件。的新证据 含有半胱天冬酶募集结构域（ASC）的凋亡相关斑点样蛋白的释放-斑点 从小胶质细胞中提取的DNA为AD中炎性小体激活提供了进一步的证据。重要的是，ASC- 具有朊病毒样特性的斑点有助于先天免疫反应的有害作用 由炎性小体介导。拟议研究的总体目标是确定机制 潜在的TBI诱导的炎性小体活化作为AD的风险因素，并评估靶向 治疗方法，以改善该患者人群的结局。我们的核心假设是， AD中炎性小体激活通过一种机制增强TBI诱导的炎症，该机制部分由 细胞外囊泡（EV）含有炎性体蛋白和ASC斑点积累，这有助于 AD病理学恶化和记忆障碍为了验证这一假设，将实现以下目标： 1）确定有害影响的时间分布和机制 目的2）探讨异常炎性小体在阿尔茨海默病（AD）发病机制中的作用 激活和ASC斑点作为TBI对脑损伤的有害作用的潜在机制。 3）观察炎性小体抑制剂和ASC-speck治疗AD小鼠的疗效 在WT和AD转基因小鼠中，TBI后的组织病理学和行为结果。的 拟议中的研究将提供关于AD的特定遗传风险因素如何增加TBI的新信息- 诱导神经退行性过程，并导致AD相关的病理和进行性认知 下降此外，这些研究将推动目前炎性小体研究进入AD/ADRD领域， 阐明TBI如何导致神经退行性疾病发作的新机制， 为评估针对异常炎性体激活的治疗干预提供了新的方向 在AD转基因小鼠中TBI后，用于潜在的临床翻译。