Neuroinflammation, Inflammatory Challenge, and Memory

神经炎症、炎症挑战和记忆

• 批准号: 8811076
• 负责人: STEVEN F MAIER
• 金额: $ 40.65万
• 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 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811076
• 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; Relative (related person); Research; Role; Signal Transduction; Synaptic plasticity; TLR2 gene; Targeted Research; Testing; Therapeutic Intervention; Time; Toll-Like Receptor 2; 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）：随着衰老，认知能力会逐渐下降。然而，人们经常注意到，老年人的认知能力下降通常会急剧发生，并且这些下降通常发生在涉及外周炎症/先天免疫细胞激活的事件（手术、病毒或细菌感染、损伤）之前。重要的是，即使从这种衰退中恢复过来，它们的发生也是长期痴呆症发展的诱发因素。这种与衰老相关的认知能力下降的原因尚不清楚，长期目标是了解所涉及的机制并开发适当的疗法。 在过去的拨款期间，我们验证了这一过程的动物模型，提出了一套机械假设来解释这一现象，并提供了初步的支持证据。在过去的拨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。已提出的假设涉及几个步骤：1）外周炎症事件向大脑发出信号。 2) 特定大脑区域的小胶质细胞被激活，作为来自外周的“我生病/受伤”信号诱导的大脑级联事件的一部分，并且小胶质细胞产生炎症介质，例如白细胞介素-1 (IL-1)。因此，外周炎症导致神经炎症。 3) 炎症介质，特别是 IL-1，可以干扰海马体等区域的神经可塑性（例如，长期增强，LP），从而破坏海马体长期记忆形成等过程。 IL-1 可以直接或通过干扰已知对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。我们已经并将继续测试这样的假设：IL-1 的大量和长期升高会干扰脑源性神经营养因子 (BDNF) 转录和翻译后处理，并且 BDNF 被广泛认为是突触可塑性和记忆的关键介质。 4) 衰老会引发小胶质细胞或使其变得敏感。这是关于衰老的关键论断。在神经退行性疾病期间，小胶质细胞明显发炎，因为它们的表型已转变为持续产生炎症分子。在衰老前的衰老过程中，小胶质细胞表现出上调的激活标记，但它们通常不会产生持续水平升高的炎症产物，例如 IL-1。然而，如果受到刺激，它们会产生大量的炎症产物，并且会持续很长时间。 5）因此，外周炎症应导致老年人出现过度的神经炎症反应，我们已经证明情况确实如此。 6) 老年受试者在外周炎症期间大脑 IL-1 的增加量和持续时间夸大，会长时间干扰认知过程，例如记忆。在这里，这些都将被测试。在这里，我们探讨小胶质细胞随年龄的敏感性的本质、其原因以及 它可以治愈。我们还确定这些疗法是否可以预防 IL-1、BDNF 和记忆衰退。