Role of inflammasomes in Alzheimer's Disease

炎症小体在阿尔茨海默病中的作用

• 批准号: 10167924
• 负责人: Douglas T Golenbock
• 金额: $ 28.01万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10167924
• 关键词: 2019-nCoV; Abeta clearance; Acceleration; Acute; Admission activity; Affect; Air; Alzheimer' s Disease; Amyloid beta-Protein; Automobile Driving; Behavioral; Brain; COVID-19; Cell Death; Cleaved cell; Clinical Research; Dementia; Deposition; Development; Disease; Disease Progression; Enrollment; Evaluation; Frontotemporal Dementia; Health; Hour; Human; Immune; Impaired cognition; Infection; Inflammasome; Inflammation; Inflammatory; Interleukin-18; Interleukin-6; Intubation; Knockout Mice; Magnetic Resonance Imaging; Measures; Mechanical ventilation; Memory impairment; Molecular; Morphology; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic; Neurologic Symptoms; Neuron-Specific Enolase; Outpatients; Pathology; Patients; Pharmacologic Substance; Phase; Phosphorylation; Plasma; Pneumonia; Pressor Support; Process; Prospective cohort; Protein Family; Roentgen Rays; Role; Seizures; Serum; TNF gene; Time; Ventilator; Virus Diseases; Work; brain morphology; cognitive testing; cytokine; cytokine release syndrome; design; genetic signature; inhibitor/antagonist; innate immune pathways; monocyte; nervous system disorder; neurofilament; neuroinflammation; neuron loss; novel; pandemic disease; peripheral blood; prevent; tau Proteins; tau aggregation; therapeutic target; transcriptome sequencing; translational approach

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.

项目摘要 R 01 AG 059752 -03的补充： 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进展的分子机制尚不清楚 定义了我们发现AD和FTD患者均存在炎性小体活化的证据， 他们的大脑我们还发现，全身炎症促进AD疾病，并增加AD患者的免疫功能。 Ab斑块的沉积，部分是通过减少大脑中Aβ的小胶质细胞清除来实现的。该过程 依赖于炎性小体，因为NLRP 3 KO小鼠显示出明显的保护作用，几乎正常化的小胶质细胞 形态学和Aβ清除率。我们还注意到NLRP 3炎性体激活驱动tau病理学 通过诱导tau蛋白过度磷酸化。综上所述，这些观察结果表明， 炎症可能通过促进蓄积而导致神经系统疾病，特别是AD和FTD 抗体斑块和诱导tau蛋白的磷酸化和聚集在神经元缠结。 急性COVID-19与高炎症细胞因子风暴有关，超过三分之一的患者 出现神经系统症状我们认为，急性COVID-19导致的炎症将加重前 现有的神经系统疾病，如阿尔茨海默病（AD）和额颞叶痴呆（FTD）， 激活脑中的NLRP 3炎性体和下游炎性体依赖性细胞因子。 成功完成这一补充目标将阐明炎性小体产生的细胞因子的作用 在COVID-19相关的神经系统症状，并可能导致新的翻译方法， 特别是阻止这种疾病中驱动神经炎症的炎症。我们还假设， COVID-19炎症可能会加速AD和FTD患者的认知能力下降。本研究 确定治疗靶点以预防许多COVID-19中发生的神经系统疾病的潜力 住院患者，并确定COVID-19炎症对AD和FTD病理学的影响， 疾病进展。