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

描述(由申请人提供)：随着年龄的增长，认知能力会逐渐下降。尽管认知功能下降通常很轻微，而且更多的是一种滋扰，而不是一种虚弱的情况，但经常有报道称，在其他认知健康的老年人中，认知功能急剧下降，令人担忧。这些下降通常发生在导致外周炎症的事件之后(例如感染、手术或受伤)。外周免疫刺激 已知会在老年人的大脑中引起夸大和持续的神经炎性反应，这些变化可能是由小胶质细胞介导的。衰老但尚未衰老的动物的小胶质细胞对炎症挑战“敏感”。也就是说，虽然老年动物的小胶质细胞基本上不会更具炎症性，但它们对免疫激活的反应是在很长一段时间内释放过多的炎症信号。与年龄相关的认知障碍似乎依赖于这些升高的神经炎性反应，特别是IL1的升高。重要的是，生产成熟的IL1蛋白通常需要组装一个炎症体，其中研究最多的是NLRP3炎症体。炎性小体是激活caspase1的多蛋白复合体，导致前-IL1裂解成成熟形式。NLRP3炎症体的激活是独一无二的，需要两个信号。在第一步(“启动”)中，NLRP3的转录/翻译是由微生物内源信号诱导的。一旦表达了NLRP3蛋白，炎症小体就可以被各种因素(石棉、颗粒物、葡萄糖)组装并激活。NLRP3炎性小体存在于小胶质细胞中，并具有NLRP3启动镜像小胶质细胞敏化的许多特征。事实上，启动和致敏的特点都是缺乏炎症信号的基础差异，而是免疫刺激后的夸大反应。最近的证据表明，糖皮质激素能迅速诱导NLRP3的表达。糖皮质激素似乎特异性地启动了NLRP3，因为需要第二个NLRP3激活信号来诱导IL1蛋白。老年大鼠海马区皮质酮浓度升高。因此，我们在这里提出，老年脑中海马糖皮质激素的升高启动了NLRP3炎症体，导致了致敏的炎症状态。一旦暴露在免疫刺激下，衰老的小胶质细胞就会产生夸大的IL-1水平。白介素1继而引发一系列炎症反应，导致认知障碍。为了确定NLRP3在年龄相关认知障碍中的作用，我们提出了以下三个具体目标。在目标I中，我们将研究NLRP3在中枢神经系统的启动和激活，并确定NLRP3启动是否起源于小胶质细胞和TLR4依赖。在AIM II中，我们将确定阻断NLRP3启动是否能防止老年大鼠在外周免疫挑战后升高的神经炎症和认知障碍。最后，在目标III中，我们将确定糖皮质激素是否介导了老年大鼠NLRP3的启动，并确定自愿运动是否可以使海马区皮质酮浓度正常化，从而阻止NLRP3的启动。

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.