The role of the NLRP3 inflammasome in aging-associated cognitive impairments

NLRP3炎性体在衰老相关认知障碍中的作用

• 批准号: 8874737
• 负责人: Laura K Fonken
• 金额: $ 5.42万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874737
• 关键词: Adaptor Signaling Protein; Age; Age-associated memory impairment; Aging; Amyloid; Animals; Asbestos; Atrophic; Behavior; Brain; Brain region; Cells; Corticosterone; Dementia; Deposition; Development; Drops; Elderly; Event; Exercise; Exposure to; Genetic Transcription; Glucocorticoids; Glucose; Goals; Hippocampus (Brain); Immune; Impaired cognition; Impairment; Individual; Infection; Inflammation; Inflammatory; Injury; Interleukin-1; Laboratories; Lead; Learning; Mediating; Memory; Memory Loss; Memory impairment; Mental Depression; Microglia; Minor; Myocardial Infarction; Neuraxis; Neurodegenerative Disorders; Operative Surgical Procedures; Particulate Matter; Pathway interactions; Peripheral; Population; Production; Proteins; Rattus; Reporting; Role; Signal Transduction; Stimulus; TLR2 gene; TLR4 gene; Testing; Time; Translations; Work; age related; aged; aging brain; aging hippocampus; behavioral response; cognitive function; cytokine; experience; immune activation; in vivo; microbial; neuroinflammation; neurotrophic factor; prevent; procaspase-1; protein complex; public health relevance; response; senescence; sensor

DESCRIPTION (provided by applicant): Gradual cognitive decline occurs as people age. Although cognitive decline is typically minor and represents more of a nuisance than a debilitating condition, there are frequent reports of alarmingly precipitous drops in cognitive function in otherwise cognitively healthy aged individuals. These drops typically follow events that induce peripheral inflammation (e.g. infection, surgery, or injury). Peripheral immune stimuli are known to cause exaggerated and prolonged neuroinflammatory responses in the aged brain, and these changes are likely mediated by microglia. Microglia of aged but not yet senescent animals are "sensitized" to inflammatory challenges. That is, while microglia from aged animals are not basally more inflammatory, they respond to immune activation by releasing excess inflammatory signals for a prolonged period of time. Age-associate cognitive impairments appear dependent on these heightened neuroinflammatory responses and particularly elevations in IL1¿. Importantly, the production of mature IL1¿ protein generally requires the assembly of an inflammasome, with the NLRP3inflammasome the most studied. Inflammasomes are multi-protein complexes that activate caspase1, leading to the cleavage of pro-IL1 into its mature form. The NLRP3 inflammasome is unique in its activation, requiring two signals. In the first ("priming") step, NLRP3 transcription/translation is induced by a microbial o endogenous signal. Once NLRP3 protein is expressed, the inflammasome can then be assembled and activated by a variety of factors (asbestos, particulate matter, glucose). The NLRP3 inflammasome is present in microglia and many features of NLRP3 priming mirror microglia sensitization. Indeed, both priming and sensitization are characterized by a lack of basal differences in inflammatory signals but an exaggerated response following immune stimulation. Recent evidence indicates that glucocorticoids rapidly induce NLRP3 expression. Glucocorticoids appear to specifically prime NLRP3, as a second NLRP3 activating signal is required to induce IL1¿ protein. Aged rats display elevated hippocampal corticosterone concentrations. Therefore, here we propose that elevated hippocampal glucocorticoids in the aged brain prime the NLRP3 inflammasome leading to a sensitized inflammatory state. Upon exposure to an immune stimulus, aged microglia then produce exaggerated levels of IL1¿. IL1¿ in turn initiates a heightened inflammatory cascade resulting in cognitive impairments. To determine the role of NLRP3 in age-associated cognitive impairments we propose the following three specific aims. In Aim I we will characterize NLRP3 priming and activation in the central nervous system and determine whether NLRP3 priming is microglial in origin and TLR4 dependent. In Aim II we will determine whether blocking NLRP3 priming prevents elevated neuroinflammation and cognitive impairments in aged rats following a peripheral immune challenge. Finally, in Aim III we will establish whether glucocorticoids mediate NLRP3 priming in aged rats and determine if voluntary exercise can normalize hippocampal corticosterone concentrations thereby preventing NLRP3 priming.

描述（由申请人提供）：随着年龄的增长，认知能力逐渐下降，尽管认知能力下降通常很轻微，而且比使人衰弱的情况更令人烦恼，但经常有报道称，在其他方面认知健康的老年人中，认知功能急剧下降。这些下降通常发生在诱发外周炎症的事件（例如感染、手术或外周免疫刺激）之后。 已知会在衰老的大脑中引起过度和长期的神经炎症反应，这些变化可能是由小胶质细胞介导的，老年但尚未衰老的动物的小胶质细胞对炎症挑战“敏感”，而来自老年动物的小胶质细胞基本上不敏感。炎症性更强，它们通过长时间释放过量的炎症信号来响应免疫激活，与年龄相关的认知障碍似乎依赖于这些丰富的神经炎症反应，特别是 IL1 的升高。重要的是，成熟IL1的产生蛋白质通常需要炎症小体的组装，其中研究最多的是NLRP3炎症小体。炎症小体是激活caspase1的多蛋白复合物，导致IL1前体裂解成其成熟形式。NLRP3炎症小体的激活是独特的，需要两个。在第一步（“启动”）中，NLRP3 转录/翻译由微生物内源信号诱导。 NLRP3 炎症小体存在于小胶质细胞中，并且 NLRP3 启动镜像小胶质细胞致敏的许多特征。其特点是炎症信号缺乏基础差异，但免疫刺激后反应过度，最近的证据表明糖皮质激素会迅速诱导 NLRP3。糖皮质激素似乎特异性启动 NLRP3，因为需要第二个 NLRP3 激活信号来诱导 IL1¿老年大鼠的海马皮质酮浓度升高，因此，老年大脑中的糖皮质激素升高，导致 NLRP3 炎症小体在暴露于免疫刺激后，产生高水平的 IL1¿ .IL1¿为了确定 NLRP3 在与年龄相关的认知障碍中的作用，我们提出了以下三个具体目标，我们将描述中枢神经系统中 NLRP3 的启动和激活。 NLRP3 引发起源于小胶质细胞并且依赖于 TLR4，在 Aim II 中，我们将确定阻断 NLRP3 引发是否可以预防老年大鼠神经炎症和认知障碍的升高。最后，在目标 III 中，我们将确定糖皮质激素是否介导老年大鼠的 NLRP3 启动，并确定自愿运动是否可以使海马皮质酮浓度正常化，从而防止 NLRP3 启动。