Role of inflammasomes in Alzheimer's Disease

项目摘要 R01 AG059752-03补充说明： 神经炎症是阿尔茨海默病(AD)和额颞叶痴呆的重要组成部分 (FTD)。然而，炎症调节AD和FTD进展的分子机制并不是 已定义。我们发现，AD和FTD患者均有炎症小体激活的证据。 他们的大脑。我们还发现，全身炎症促进了阿尔茨海默病，增加了 抗体斑块的沉积，部分是通过减少小胶质细胞对Aβ的清除而实现的。这一过程是 依赖炎性小体，因为NLRP3 KO小鼠显示出接近正常的小胶质细胞的明显保护作用 形态和β检测结果。我们还注意到，NLRP3炎症体激活驱动tau病理 通过诱导tau蛋白过度磷酸化。综上所述，这些观察结果表明，系统性 炎症可能通过促进积聚而导致神经系统疾病，特别是AD和FTD 并诱导神经原纤维缠结中tau的磷酸化和聚集。 急性新冠肺炎与高炎性细胞因子风暴有关，超过三分之一的患者 出现神经症状。我们认为，急性新冠肺炎驱动的炎症将加剧Pre 现有的神经疾病，如阿尔茨海默病(AD)和额颞部痴呆(FTD)通过 激活大脑中的NLRP3炎症体和下游炎症体依赖的细胞因子。 这一补充目标的成功完成将阐明炎症体产生的细胞因子的作用 在新冠肺炎中，患者会出现相关的神经系统症状，并可能导致旨在 具体地说，就是阻止导致这种疾病的神经炎症的炎症。我们还假设 新冠肺炎炎症可能会加速AD和FTD患者的认知功能下降。这项研究有 确定治疗靶点以预防许多新冠肺炎中发生的神经疾病的可能性 并确定新冠肺炎炎症对AD和FTD病理和病理的影响 疾病的发展。

PROJECT ABSTRACT Supplement to R01 AG059752-03: Neuroinflammation is an important component of Alzheimer's disease (AD) and Fronto-temporal dementia (FTD). However, the molecular mechanism by which inflammation modulates AD and FTD progression are not defined. We discovered that both AD and FTD patients uniformly have evidence of activated inflammasomes in their brains. We have also found that systemic inflammation promotes AD disease and increases the deposition of Ab plaques, in part by reducing microglial clearance of Aβ in the brain. This process was dependent on inflammasomes, as NLRP3 KO mice showed clear protection with nearly normalized microglial morphology and Aβ clearance. We have also noted that NLRP3 inflammasome activation drives tau pathology by inducing tau hyper-phosphorylation. Taken together, these observations suggest that systemic inflammation likely contributes to neurologic diseases, particularly AD and FTD, by promoting the accumulation of Ab plaques and inducing the phosphorylation and aggregation of tau in neurofibrillary tangles. Acute COVID-19 is associated with a hyper-inflammatory cytokine storm and more than a third of patients develop neurologic symptoms. We believe that acute COVID-19 driven inflammation will aggravate pre- existing neurologic disorders, such as Alzheimer’s Disease (AD) and fronto-temporal dementia (FTD) via activation NLRP3 inflammasomes and downstream inflammasome-dependent cytokines in the brain. Successful completion of this supplemental Aims will elucidate the role of inflammasome-generated cytokines in COVID-19 associated neurologic symptoms and could result in novel translational approaches designed to specifically halt the inflammation that drives neuroinflammation in this disease. We also hypothesize that COVID-19 inflammation can potentially accelerate cognitive decline in AD and FTD patients. This study has the potential to identify therapeutic targets to prevent the neurologic disorders that occur in many COVID-19 hospitalized patients and to determine the impact of COVID-19 inflammation on AD and FTD pathology and disease progression.