Neuroinflammatory mechanisms underlying sepsis-induced cognitive dysfunction

摘要 老年人中较高的脓毒症患病率也与多种类型肺炎的诊断率增加有关 痴呆症包括阿尔茨海默病和相关痴呆(ADRD)。慢性损伤包括改变 在记忆和注意力方面，情绪功能和神经肌肉力量分别对 病人和家属。这种持续性损害背后的确切机制尚不清楚，但数据支持其中的作用 用于感染后慢性激活的小胶质细胞。对这一危重时期神经系统变化的认识 由于缺乏合适的动物模型和较短的实验终点，时间段受到阻碍。行为 评估可能会被不活跃的精神错乱状态和疾病行为严重混淆，而且许多 研究是在年轻动物身上进行的，而不是在老年动物身上进行的，没有额外的与AD相关的神经病理学 进一步限制了解释和预测能力。我们将应对每一个挑战，并测试 认为年龄和阿尔茨海默病的神经病理倾向于大脑的主要假说 导致神经元损伤更大，小胶质细胞激活时间延长，认知结果变差 败血症。此外，我们假设老年人的小胶质细胞有更强烈的炎症反应。 以及降低导致持续性认知障碍的炎症反应的能力， 特别是在存在与AD相关的额外神经病理的情况下。我们的三个目标将在 年轻成年(3个月)和老龄小鼠(最多18个月)，体内数据将由体外支持 电生理学、免疫组织化学和分子生物学方法。我们将评估我们的主要成果 在疾病康复后最多90天。在目标1中，我们将演示风险增加的程度 老年人脓毒症后持续性认知损害与长期神经炎的对比研究 敬年幼的动物。我们将使用盲肠浆液注射在18个月龄的小鼠身上使用啮齿类动物来诱导败血症。 模型概括了急性脑功能障碍的主要定义特征，包括：急性 神经炎性反应，脑电模式紊乱，一系列认知和行为障碍 神经肌肉区域和受损的海马长时程增强。在目标2中，我们将直接检查 小胶质细胞在脓毒症后持续性认知损害中的作用 小胶质细胞、全组织和单细胞的生物标志物、免疫组织化学形态定量 核糖核酸正在接近。在目标3中，我们将确定AD神经病理对脓毒症的影响程度。 诱发的认知障碍和脑功能障碍。我们将比较行为结果和小胶质细胞 在两种不同的AD小鼠模型上的反应，以测试在存在的情况下增加对CS的敏感性的可能性 常见的阿尔茨海默病神经病理和基因变异。

ABSTRACT Higher prevalence of sepsis in older individuals is also linked to increased rate of diagnoses for multiple types of dementia including Alzheimer’s disease and related dementias (ADRD). Chronic impairments include changes in memory and attention, emotional function and neuromuscular strength which each have a major impact on patients and families. Exact mechanisms underlying this persistent damage are unknown but data support a role for chronically activated microglia following infection. Understanding of neurological changes during this critical time period is hampered by a lack of appropriate animal models and short experimental endpoints. Behavioral assessments can be severely confounded by hypoactive delirious states and sickness behaviors, and many studies have been conducted in young rather than aged animals, without additional AD-relevant neuropathology further limiting interpretive and predictive power. We will address each of these challenges and test the overarching hypothesis that overarching hypothesis that age and AD neuropathology predispose the brain to greater neuronal damage, prolonged microglial activation and poorer cognitive outcomes following sepsis. Further, we hypothesize that microglia of older adults have a more robust inflammatory response and a reduced ability to downregulate inflammation leading to persistent cognitive impairment, particularly in the presence of additional AD-relevant neuropathology. Our three aims will be conducted in young adult (3 months) and aged mice (up to 18 months), and in vivo data will be supported by ex vivo electrophysiology, immunohistochemistry and molecular biology approaches. We will assess our key outcomes up to 90 days following recovery from illness. In Aim 1 we will demonstrate the extent of increased risk for persistent cognitive impairment and prolonged neuroinflammation following sepsis in aged compared to young animals. We will use a cecal slurry injection to induce sepsis in mice up to 18 months using a rodent model that recapitulates the major defining features of acute brain dysfunction including: acute neuroinflammatory response, disrupted EEG patterns, behavioral deficits across a range of cognitive and neuromuscular domains, and impaired hippocampal long-term potentiation. In Aim 2 we will directly examine the role of microglia in persistent cognitive impairment following sepsis using clinically relevant biomarkers, immunohistochemistry morphological quantification of microglia and whole tissue and single cell RNA approaches. In Aim 3 we will determine the extent to which AD neuropathology contributes to sepsis- induced cognitive impairment and brain dysfunction. We will compare behavioral outcomes and microglial response in two different mouse models of AD to test the potential for increased sensitivity to CS in the presence of common AD neuropathology and gene variants.