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

创伤性脑损伤是阿尔茨海默病和阿尔茨海默病的危险因素 疾病相关性痴呆(AD/ADRD)。尽管在评估方面已经做了很多工作 颅脑损伤与阿尔茨海默病的病理生理机制，二者之间的关系尚不清楚 完全理解。炎症在颅脑损伤和神经退行性变病理生理中的作用 在实验和临床文献中已有疾病的报道。相应地，TBI和 神经退行性疾病有许多共同的病理和免疫学特征，表明潜在的 对于治疗策略至关重要的关系被开发出来。最近，我们的实验室以及 另一些研究则有助于阐明炎症小体异常信号在脑外伤发病机制中的重要性。 在老化的大脑中。这些发现表明，先天炎症反应在 阿尔茨海默病等神经退行性疾病的多种病理生理事件。新的证据表明 含有半胱氨酸天冬氨酸酶招募结构域(ASC-SPECS)的凋亡相关SPECK样蛋白的释放 来自小胶质细胞的研究为阿尔茨海默病的炎症体激活提供了进一步的证据。重要的是，ASC- 具有普恩病毒性质的斑点有助于天然免疫反应的有害影响。 由炎性小体调节。拟议研究的总体目标是确定机制 脑损伤后炎性小体激活是AD的危险因素及靶向评估 改善这一患者群体预后的治疗方法。我们的中心假设是 阿尔茨海默病患者炎性小体激活增强脑损伤后炎症反应的机制部分是通过 细胞外小泡(EV)含有炎症体蛋白和ASC-SPECK积聚，这有助于 导致阿尔茨海默病病理和记忆障碍恶化。为了检验这一假设，以下目标将是 追求：目标1)确定有害影响的时间分布和潜在机制 脑外伤对阿尔茨海默病小鼠炎性小体激活的影响；目的2)探讨异常炎性小体的作用 小胶质细胞的激活和ASC-SPEKS是脑外伤损伤的潜在机制 目的3)确定炎性小体抑制和ASC-SPECK的治疗作用。 WT和AD转基因小鼠脑外伤后组织病理学和行为学结果的形成。这个 拟议的研究将提供新的信息，说明AD的特定遗传风险因素如何可能增加TBI。 诱发神经退行性变过程并导致AD相关的病理和进行性认知 拒绝。此外，这些研究将推动目前对AD/ADRD领域的炎症学研究 阐明脑损伤如何导致神经退行性疾病的新机制，以及 为评价针对炎性小体异常激活的治疗干预提供新的方向 在AD转基因小鼠的脑损伤后有可能移植到临床。

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.