Neuroinflammation, Inflammatory Challenge, and Memory

描述（由申请人提供）：随着年龄的增长，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往往是突然发生的，而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一个诱发因素。这种与年龄相关的认知衰退的原因尚不清楚，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，开发了一套机制假设来解释这一现象，并提供了初步的支持证据。在过去的资助期间进行的工作和这里提出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。这一假说包括以下几个步骤：1)外周炎症事件向大脑发出信号。2)当来自外周的“我生病了/受伤了”信号在大脑中引起一系列事件时，特定脑区的小胶质细胞被激活，小胶质细胞产生炎症介质，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，可以干扰海马等区域的神经可塑性（如长期增强，LP），因此破坏海马长期记忆形成等过程。IL-1可以通过干扰其他已知的对神经可塑性和记忆形成至关重要的过程直接做到这一点。我们已经并将继续测试IL-1的大量和长期升高干扰脑源性神经营养因子（BDNF）转录和翻译后加工的假设，BDNF被广泛认为是突触可塑性和记忆的关键介质。4)衰老启动或使小胶质细胞敏感。这是关于衰老的关键论断。在神经退行性疾病期间，小胶质细胞明显炎症，因为它们的表型已经转变为持续产生炎症分子。在衰老前期，小胶质细胞的激活标记上调，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，它们会产生大量的炎症产物，并持续很长时间。5)因此，外周炎症应该导致老年人神经炎症反应的夸大，我们已经证明了这一点。6)老龄受试者在外周炎症期间脑IL-1升高的量和持续时间会对记忆等认知过程造成较长时间的干扰。在这里，这些都将被测试。在这里，我们探讨小胶质细胞增敏的性质与年龄，其原因，和

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.