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: 8781071
• 负责人: Laura K Fonken
• 金额: $ 5.15万
• 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/8781071
• 关键词: Adaptor Signaling Protein; Age; Age-associated memory impairment; Aging; Amyloid; Animals; Asbestos; Atrophic; Behavior; Behavioral; 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 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; 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）：随着人们年龄的增长，认知能力会逐渐下降。虽然认知能力下降通常是轻微的，而且与其说是一种使人衰弱的状况，不如说是一种麻烦，但经常有报道称，在认知健康的老年人中，认知功能的急剧下降令人震惊。这些滴剂通常是在引起外周炎症（如感染、手术或损伤）的事件后滴入的。外周免疫刺激