Targeting age-related neuroinflammation and postoperative cognitive decline: a microbial-based approach

项目摘要/摘要 术后认知功能下降(POCD)是一种尤其困扰老年人的衰弱状况。 (约40%的老年外科患者发生POCD)。POCD极大地增加了发病率、死亡率、 以及阿尔茨海默氏症的发展。大脑中的炎症(“神经炎症”)，它变成 随着年龄的增长，更易激动或更容易“启动”，可能会导致POCD。事实上，免疫系统发生了实质性的变化 随着年龄的增长，免疫系统与中枢神经系统(CNS)进行通信，并改变其功能 局部中枢神经系统免疫细胞，如小胶质细胞。在现代社会，异常清洁的环境会减少暴露。 到有助于形成免疫调节回路的环境和共生微生物。重新引入 过度无菌环境中的微生物可以改善免疫调节，平息多动症 炎症反应。尽管特定的小微生物具有治疗潜力，但很少有研究评估 以微生物为基础的治疗策略是否针对中枢神经系统并在老年人口中有效。这样的一个 广泛分布的土壤分枝杆菌是一种在衰老过程中有利于神经炎症的微生物 Vacae(母牛分支杆菌)，被批准用于人类治疗，并改善其他患者的生活质量 环境(过敏和癌症)。因此，这一提议的中心假设是母牛分枝杆菌免疫疗法 (三次皮下注射)对老年大鼠的神经炎症和认知功能衰退有保护作用 在手术后。我们的初步结果表明，母牛分枝杆菌免疫疗法具有强大和持续的抗 老年大鼠中枢神经系统炎症活性(+IL-4)并阻断持续性促炎反应(IL-1β) 以及手术后的认知缺陷。痘苗分枝杆菌似乎能诱导有益的(抗炎)中枢神经系统 响应并重定向小胶质细胞的激活状态。母牛分枝杆菌可增强体内的免疫调节 通过改变T细胞群，并可能改变进入中枢神经系统及其周围的T细胞群 脑膜间隙引起中枢神经系统的变化。因此，这项提议涉及以下具体目标：第一， 确定疫苗分枝杆菌是否是预防年龄相关性POCD的可行的临床前靶点；第二，确定 母牛分枝杆菌诱导老年神经免疫持续保护性转移的中枢神经系统特异性机制 第三，确定母牛分枝杆菌如何将其抗炎信号传递给大脑。这 研究是创新的：基于微生物的治疗可以有效地改善外周炎症，但 几乎没有关于微生物治疗是否可以防止损害的研究 神经炎。我们的总体长期目标是阐明细胞和分子机制。 潜在的神经炎性启动；了解小胶质细胞功能如何向病理性转变 与年龄的反应；并确定这些神经免疫变化如何劫持行为功能。

Project Summary/Abstract Postoperative cognitive decline (POCD) is a debilitating condition that particularly plagues aged individuals (~40% of elderly surgical patients develop POCD). POCD substantially increases the risk of morbidity, mortality, and the development of Alzheimer’s disease. Inflammation in the brain (“neuroinflammation”), which becomes more excitable or “primed” with age, may cause POCD. Indeed, substantial changes in the immune system occur with age and the immune system communicates with the central nervous system (CNS) and alters the function of local CNS immune cells such as microglia. In modern society, unusually clean conditions decrease exposure to environmental and commensal microorganisms that help shape immunoregulatory circuits. Reintroduction of microorganisms in an overly sterile environment can improve immunoregulation and quell hyperactive inflammatory responses. Despite the therapeutic potential of specific small microbes, few studies have assessed whether microbial-based treatment strategies target the CNS and are effective in aged populations. One such microbe that could benefit neuroinflammation in aging is the widely distributed soil bacterium Mycobacterium vaccae (M. vaccae), which is approved for therapeutic use in humans and improves quality of life in other contexts (allergy and cancer). Thus, the central hypothesis of this proposal is that M. vaccae immunotherapy (three subcutaneous injections) will protect against primed neuroinflammation and cognitive decline in aged rats following surgery. Our preliminary results indicate that M. vaccae immunotherapy has robust and sustained anti- inflammatory activity (+IL-4) in the CNS of aged rats and blocks persistent pro-inflammatory responses (IL-1β) and cognitive deficits following surgery. M. vaccae appears to induce a beneficial (anti-inflammatory) CNS response and redirect the activation state of microglia. M. vaccae enhances immunoregulation in the body through altering T cell populations and may shift the population of T cells accessing the CNS and surrounding meningeal space to elicit changes in the CNS. Thus, this proposal addresses the following specific aims: first, establish whether M. vaccae is a viable pre-clinical target for preventing age-associated POCD; second, identify the CNS-specific mechanisms by which M. vaccae induces a sustained protective shift in the aged neuroimmune environment; and third, establish how M. vaccae communicates its anti-inflammatory signal to the brain. This research is innovative: microbial-based treatments can effectively improve peripheral inflammation, yet there is almost no research investigating whether microbial-based treatments can protect against damaging neuroinflammation. Our overall long-term goals are to elucidate the cellular and molecular mechanisms underlying neuroinflammatory priming; to understand how microglia function transitions toward pathological responses with age; and to determine how these neuroimmune alterations hijack behavioral function.