Neuroinflammation, Inflammatory Challenge, and Memory

神经炎症、炎症挑战和记忆

• 批准号: 9022380
• 负责人: STEVEN F MAIER
• 金额: $ 41.91万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9022380
• 关键词: Accounting; Adrenal Glands; Age; Age-associated memory impairment; Aging; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Attention; Bacterial Infections; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cells; Clinical; Cognitive; Corticosterone; Data; Dementia; Deterioration; Development; Drops; Effector Cell; Escherichia coli Infections; Event; Genetic Transcription; Glucocorticoids; Goals; Grant; Hippocampus (Brain); Immediate-Early Genes; Immune; Immune Cell Activation; Impaired cognition; Impairment; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Interleukin-1 Receptors; Intervention; Laparotomy; Lead; Ligands; Long-Term Potentiation; Mediating; Mediator of activation protein; Memory; Memory impairment; Microglia; Nature; Neurodegenerative Disorders; Neuronal Plasticity; Operative Surgical Procedures; Organism; Peripheral; Phenotype; Play; Predisposing Factor; Predisposition; Process; Production; Proteins; Recovery; Research; Role; Signal Transduction; Synaptic plasticity; TLR2 gene; Targeted Research; Testing; Therapeutic Intervention; Time; Toll-like receptors; Virus Diseases; Work; age effect; age related; aging brain; cognitive process; design; healthy aging; immune activation; injured; interest; long term memory; neuroinflammation; novel; prevent; receptor; receptor function; response; senescence

DESCRIPTION (provided by applicant): Gradual cognitive decline does develop with senescence. However, it has frequently been noted that cognitive declines in older individuals often occur precipitously, & that these drops are typically preceded by events (surgery, viral or bacterial infection, injury) that involve peripheral inflammation/innate immune cell activation. Importantly, even when there is recovery from such declines, their occurrence is a predisposing factor to the development of long-term dementia. The cause(s) of this type of aging-related cognitive decline are unknown, & the long-term goal is to understand the mechanisms involved & develop appropriate therapies. During the past grant period we validated an animal model of this process, developed a mechanistic set of hypotheses to account for this phenomenon, & provided preliminary evidence in support. Work conducted during the past grant period & the further work here proposed is directed at understanding this phenomenon & its causes, as well as the discovery of therapeutic interventions. The hypothesis that has been developed involves several steps: 1) Peripheral inflammatory events signal the brain. 2) Microglia in specific brain regions become activated as part of the cascade of events in the brain induced by the "I am sick/injured" signal from the periphery, & the microglia produce inflammatory mediators, such as interleukin-1 (IL-1). Thus, peripheral inflammation leads to neuroinflammation. 3) Inflammatory mediators, particularly IL-1, can interfere with neural plasticity (e.g., long-term potentiation, LP) in regions such as the hippocampus, & therefore disrupt processes such as hippocampal long-term memory formation. IL-1 can do so directly & by interfering with other processes known to be critical for neural plasticity & memory formation. We have, & continue to test the hypothesis that large & prolonged elevations of IL-1 interfere with brain derived neurotrophic factor (BDNF) transcription & post-translational processing, & BDNF is well accepted as a critical mediator of synaptic plasticity & memory. 4) Aging primes or sensitizes microglia. This is the key assertion with regard to aging. During neurodegenerative disease microglia are overtly inflammatory in that their phenotype has shifted to ongoing production of inflammatory molecules. During pre-senescent aging, microglia show upregulated markers of activation, but they do not typically produce increased ongoing levels of inflammatory products such as IL-1. However, if stimulated they produce exaggerated quantities of inflammatory products, & do so for prolonged periods. 5) Thus, peripheral inflammation should lead to an exaggerated neuroinflammatory response in aging individuals, & we have demonstrated that this is the case. 6) The exaggerated amount & duration of the brain IL-1 increase in aging subjects during peripheral inflammation should interfere with cognitive processes such as memory for a prolonged period of time. Here these will all be tested. Here we explore the nature of microglia sensitization with age, its causes, and its cures. We also determine whether these cures prevent IL-1, BDNF, and memory deterioration.

描述（由申请人提供）：逐渐认知下降的确会随着衰老而发展。但是，经常注意到，老年人的认知下降经常发生，并且这些滴剂通常是在涉及周围炎症/先天免疫细胞激活的事件之前（手术，病毒或细菌感染，损伤）。重要的是，即使从这种下降中恢复过来，它们的发生也是长期痴呆症发展的诱人因素。这种类型的与衰老相关的认知下降的原因是未知的，长期目标是了解涉及的机制并开发适当的疗法。 在过去的赠款期间，我们验证了该过程的动物模型，开发了一组机械的假设来解释这一现象，并提供了支持的初步证据。在过去的赠款期间进行的工作和这里提出的进一步工作旨在了解这种现象及其原因，以及发现治疗干预措施。已经开发的假设涉及多个步骤：1）外周炎症事件标志着大脑。 2）特定大脑区域中的小胶质细胞被激活，这是由周围的“我生病/受伤的”信号引起的大脑级联反应的一部分，而小胶质细胞产生炎症介质，例如白介素-1（IL-1）。因此，周围炎症会导致神经炎症。 3）炎症介质，尤其是IL-1，可以干扰海马等地区的神经可塑性（例如，长期增强，LP），因此破坏了海马长期记忆形成等过程。 IL-1可以直接和干扰已知对于神经可塑性和记忆形成至关重要的其他过程来做到这一点。我们已经并继续检验了以下假设：IL-1的大升高干扰脑衍生的神经营养因子（BDNF）转录和翻译后处理，＆BDNF被很好地接受为突触可变性和记忆的关键介体。 4）衰老质量或使小胶质细胞敏感。这是关于衰老的关键断言。在神经退行性疾病期间，小胶质细胞公开炎症，因为它们的表型已转移到炎症分子的持续产生。在染色前衰老期间，小胶质细胞表现出上调的激活标记，但通常不会产生持续的炎症产物（如IL-1）的持续水平。但是，如果受到刺激，它们会产生夸张的炎症产物，并且会长时间进行。 5）因此，周围炎症应导致衰老个体的夸张神经炎症反应，我们已经证明了这种情况。 6）周围炎症期间，脑IL-1的夸张量和持续时间增加应干扰认知过程，例如长时间的记忆。在这里，这些都将进行测试。在这里，我们探索小胶质细胞敏化的性质，年龄，其原因和 它的治疗方法。我们还确定这些治疗方法是否可以防止IL-1，BDNF和记忆力恶化。