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（适用提供）：随着人们的年龄增长，逐渐认知下降。尽管认知能力下降通常很小，并且比令人衰弱的状况更像是滋扰，但经常有报道称，在其他认知健康的老年人中，认知功能的精确下降。这些滴水通常遵循引起周围感染的事件（例如感染，手术或损伤）。外周免疫刺激 已知会导致老化大脑的夸张和延长的神经炎症反应，这些变化很可能是由小胶质细胞介导的。年龄但尚未敏感的动物的小胶质细胞对炎症挑战“敏感”。也就是说，尽管老年动物的小胶质细胞并没有基本上炎症，但它们通过延长过多的炎症信号来反应免疫激活。年龄相关的认知障碍似乎取决于这些增强的神经炎症反应，尤其是IL1的升高，重要的是，成熟IL1¿蛋白质的产生通常需要炎症体的组装，而NLRP3Inflammasome则最多。炎性症是激活caspase1的多蛋白质复合物，导致pro-il1裂解为其成熟形式。 NLRP3炎性体的激活是独一无二的，需要两个信号。在第一个（“启动”）步骤中，NLRP3转录/翻译是由微生物O内源信号诱导的。一旦表达了NLRP3蛋白，就可以通过多种因子（石棉，颗粒物，葡萄糖）组装炎症体。 NLRP3炎症体在小胶质细胞和NLRP3启动镜小胶质细胞传感器的许多特征中呈现。实际上，启动和敏感性的特征是炎症信号缺乏基本差异，但免疫刺激后夸张的反应。最近的证据表明，糖皮质激素迅速诱导NLRP3表达。糖皮质激素似乎是特异性的NLRP3，因为需要第二个NLRP3激活信号来诱导IL1蛋白质。老年大鼠的海马皮质酮浓度升高。因此，我们在这里提出，老年大脑中海马糖皮质激素升高，导致敏感炎症状态的NLRP3炎性体质量。暴露于免疫刺激后，老化的小胶质细胞会产生夸张的IL1级水平。在AIM II中，我们将确定阻塞NLRP3启动是否可以防止外周免疫挑战后老年大鼠的神经炎症和认知障碍升高。最后，在AIM III中，我们将确定糖皮质激素培养基NLRP3是否在老年大鼠中启动，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。