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

项目总结/摘要 术后认知功能下降（POCD）是一种使人衰弱的疾病，尤其困扰老年人 （约40%的老年手术患者发生POCD）。POCD大大增加了发病率，死亡率， 和老年痴呆症的发展。大脑中的炎症（“神经炎症”）， 随着年龄的增长变得更加容易兴奋或“引发”，可能导致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）沟通并改变功能， 局部中枢神经系统免疫细胞，如小胶质细胞。在现代社会中，异常清洁的环境减少了暴露 到环境和微生物，帮助形成免疫调节回路。重新引入 过度无菌环境中的微生物可以改善免疫调节， 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 基于微生物的治疗策略是否靶向中枢神经系统，是否对老年人群有效。一个这样 一种可以促进衰老过程中神经炎症的微生物是广泛分布在土壤中的分枝杆菌 vaccae（M. vaccae），其被批准用于人类的治疗用途并改善其他人的生活质量。 过敏和癌症（Allergy and Cancer）。因此，这个建议的中心假设是M。母牛免疫疗法 （三次皮下注射）将防止老年大鼠的引发神经炎症和认知能力下降 手术后。初步结果表明，M.疫苗免疫疗法具有强大和持续的抗 炎症活性（+IL-4），并阻断持续性促炎反应（IL-1β） 和认知缺陷M.母牛似乎诱导有益的（抗炎）CNS 反应和重定向小胶质细胞的激活状态。M.牛痘增强体内免疫调节 通过改变T细胞群，并可能改变进入CNS和周围环境的T细胞群， 脑膜间隙以引起CNS的变化。因此，这项建议涉及以下具体目标：第一， 确定M.疫苗是预防年龄相关POCD的可行临床前靶点;第二， CNS特异性机制，M.疫苗诱导老年神经免疫系统的持续保护性转变 环境;第三，建立如何M。母牛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，然而， 几乎没有研究调查是否微生物为基础的治疗可以防止损害 神经炎症我们的总体长期目标是阐明细胞和分子机制 潜在的神经炎症启动;了解小胶质细胞功能如何向病理性 随着年龄的增长，以及确定这些神经免疫改变如何劫持行为功能。

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.