Neuroinflammation, Inflammatory Challenge, and Memory

描述(申请人提供)：随着年龄的增长，认知能力会逐渐衰退。然而，人们经常注意到，老年人的认知能力下降通常是突然发生的，这些下降通常发生在涉及外周炎症/先天性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，即使从这种下降中恢复过来，它们的发生也是发展为长期痴呆症的诱因。这种与衰老相关的认知功能下降的原因(S)尚不清楚，长期目标是了解其中的机制并开发适当的治疗方法。在过去的资助期间，我们验证了这一过程的动物模型，开发了一套机制假说来解释这一现象，并提供了初步的证据支持。在过去的赠款期间进行的工作&这里提议的进一步工作旨在了解这一现象及其原因，以及发现治疗干预措施。已经提出的假设包括几个步骤：1)外周炎症事件向大脑发出信号。2)脑部特定区域的小胶质细胞被激活，这是外围“我生病/受伤”信号引起的脑内一系列事件的一部分，小胶质细胞产生炎症介质，如白介素1(IL-1)。因此，外周炎症会导致神经炎症。3)炎症介质，特别是IL-1，可以干扰海马区等区域的神经可塑性(例如，长时程增强，LP)，从而扰乱诸如海马体长期记忆形成等过程。IL-1可以直接做到这一点&通过干扰其他已知对神经可塑性和记忆形成至关重要的过程。我们已经并将继续检验这一假说，即IL-1的大量和长期升高干扰了脑源性神经营养因子(BDNF)的转录和翻译后处理，BDNF被公认为是突触可塑性和记忆的关键介质。4)老化启动或敏化小胶质细胞。这是关于衰老的关键论断。在神经退行性疾病期间，小胶质细胞明显具有炎症性，因为它们的表型已经转变为正在进行的炎性分子的产生。在衰老前期，小胶质细胞表现出激活标志的上调，但它们通常不会产生持续增加的炎症产物，如IL-1。然而，如果受到刺激，它们会产生夸大数量的炎症产物，这种情况会持续很长一段时间。5)因此，外周炎症应该导致老年人的神经炎性反应被夸大，我们已经证明了这一点。6)老年患者外周炎症时脑内IL-1水平升高的幅度和持续时间过大，可能会对记忆等认知过程造成较长时间的干扰。在这里，这些都将受到考验。在这里，我们探讨了小胶质细胞增敏的本质，其原因，以及 它的治疗方法。我们还确定这些疗法是否能防止IL-1、脑源性神经营养因子和记忆退化。 与公共健康相关：认知能力的逐渐下降确实会随着年龄的增长而发展。然而，人们经常注意到，老年人的认知能力下降通常是突然发生的，这些下降通常发生在涉及外周炎症/先天性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 即使从这种下降中恢复过来，它们的发生也是发展为长期痴呆症的一个诱因。这种与衰老相关的认知功能下降的原因(S)尚不清楚，长期目标是了解其中的机制并开发适当的治疗方法。

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. PUBLIC HEALTH RELEVANCE: 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.