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，认知能力逐渐下降。虽然认知能力下降通常是轻微的，并且比使人衰弱的状况更令人讨厌，但经常有报告称，在其他认知健康的老年人中，认知功能惊人地急剧下降。这些下降通常发生在诱导外周炎症的事件（例如感染、手术或损伤）之后。外周免疫刺激 已知在老年大脑中引起过度和延长的神经炎症反应，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刺激“敏感”。也就是说，虽然来自老年动物的小胶质细胞基本上没有更多的炎症，但它们通过长时间释放过量的炎症信号来响应免疫激活。与此相关的认知障碍似乎依赖于这些增强的神经炎症反应，特别是IL 1水平的升高。重要的是，成熟IL 1？蛋白的产生通常需要炎性小体的组装，其中NLRP 3炎性小体是研究最多的。炎性小体是激活半胱天冬酶1的多蛋白复合物，导致IL 1前体裂解成其成熟形式。NLRP 3炎性体的激活是独特的，需要两个信号。在第一（“引发”）步骤中，通过微生物内源性信号诱导NLRP 3转录/翻译。一旦NLRP 3蛋白表达，炎性小体就可以被多种因素（石棉、颗粒物、葡萄糖）组装和激活。NLRP 3炎性体存在于小胶质细胞中，并且NLRP 3引发镜像小胶质细胞敏化的许多特征。事实上，引发和致敏的特征都在于炎症信号缺乏基础差异，但在免疫刺激后反应过度。最近的证据表明，糖皮质激素迅速诱导NLRP 3的表达。糖皮质激素似乎特异性地引发NLRP 3，因为诱导IL 1？蛋白需要第二个NLRP 3激活信号。老年大鼠海马皮质酮浓度升高。因此，在这里，我们提出，海马糖皮质激素在老年大脑中的升高引发NLRP 3炎性小体，导致致敏的炎症状态。当暴露于免疫刺激物时，老化的小胶质细胞会产生过量的IL 1？。IL-1反过来又引发了一个加剧的炎症级联反应，导致认知障碍。为了确定NLRP 3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。在目的I中，我们将描述NLRP 3在中枢神经系统中的启动和激活，并确定NLRP 3启动是否是小胶质细胞起源和TLR 4依赖性的。在目的II中，我们将确定阻断NLRP 3引发是否可以预防外周免疫攻击后老年大鼠神经炎症和认知障碍的升高。最后，在目的III中，我们将确定糖皮质激素是否介导老年大鼠的NLRP 3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NLRP 3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.