Neuroinflammatory mechanisms underlying sepsis-induced cognitive dysfunction

脓毒症引起认知功能障碍的神经炎症机制

• 批准号: 10835675
• 负责人: Julie Anne Bastarache
• 金额: $ 16.51万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10835675
• 关键词: Acceleration; Acute; Affect; Age; Alzheimer' s disease model; Alzheimer' s disease related dementia; American; Amyloid deposition; Animal Model; Animals; Apoptosis; Astrocytes; Attention; Behavior; Behavior assessment; Behavioral; Biological Markers; Blood Coagulation Disorders; Brain; Brain Injuries; Cell Death; Cells; Chronic; Clinical; Cognition; Cognitive; Cognitive deficits; Critical Illness; Data; Delirium; Dementia; Development; Diagnosis; Disease; Disease model; Dose; Elderly; Electroencephalography; Electrophysiology (science); Event; Family; Functional disorder; Future; Gene Expression; Genetic; Genotype; High Prevalence; Hippocampus; Immune; Immunohistochemistry; Impaired cognition; Impairment; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injections; Injury; Intensive Care Units; Intervention Studies; Learning; Length of Stay; Link; Liquid substance; Long-Term Potentiation; Measurement; Measures; Memory; Microglia; Modeling; Molecular; Molecular Biology; Monitor; Morphology; Motor; Mus; Muscle; Myelogenous; Neurologic; Neuronal Injury; Neurons; Neurophysiology - biologic function; Outcome; Oxidative Stress; Patients; Pattern; Phase; Physiological; Predisposition; Prevalence; RNA; Recovery; Research; Risk; Rodent; Rodent Model; Role; Senile Plaques; Sepsis; Severities; Slice; Survivors; Synapses; System; Testing; Time; Tissues; United States National Institutes of Health; Vulnerable Populations; aged; aging brain; behavior measurement; behavioral outcome; brain cell; brain dysfunction; care costs; cecal ligation puncture; clinically relevant; comparison control; disability; emotion regulation; emotional functioning; falls; genetic variant; glial activation; human old age (65+); hyperphosphorylated tau; in vivo; intraperitoneal; juvenile animal; mixed dementia; mortality; mouse model; neuroinflammation; neuromuscular; neuropathology; pathogen; pharmacologic; polymicrobial sepsis; protein expression; response; septic; septic patients; sex; sustained attention; synaptic pruning; systemic inflammatory response; young adult

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.

摘要 老年人中败血症的较高患病率也与多种类型败血症的诊断率增加有关。 痴呆，包括阿尔茨海默病和相关痴呆（ADRD）。慢性损伤包括 在记忆力和注意力，情绪功能和神经肌肉力量，每一个都有重大影响， 患者和家属。这种持续性损害的确切机制尚不清楚，但数据支持一个作用 感染后慢性激活的小胶质细胞了解这一关键时期的神经变化 由于缺乏合适的动物模型和实验终点较短，因此时间段受到阻碍。行为 评估可能会被活动减退的谵妄状态和疾病行为严重混淆，而且许多 在年轻而非老年动物中进行了研究，没有额外的AD相关神经病理学 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 年龄和AD神经病理学易使大脑 更大的神经元损伤，延长的小胶质细胞激活和更差的认知结果， 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， 以及下调炎症的能力降低导致持续性认知障碍， 特别是在存在额外的AD相关神经病理学的情况下。我们的三个目标将在 年轻成年小鼠（3个月）和老年小鼠（最多18个月），体内数据将得到离体实验的支持。 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 从疾病中恢复后90天内。在目标1中，我们将证明以下风险增加的程度： 老年人脓毒症后持续性认知障碍和长期神经炎症的比较 年轻的动物。我们将使用一种啮齿类动物，在长达18个月的小鼠中使用盲肠浆液注射来诱导脓毒症。 该模型概括了急性脑功能障碍的主要定义特征，包括：急性 神经炎症反应，脑电图模式中断，一系列认知和行为缺陷， 神经肌肉结构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障碍中的作用 生物标志物，小胶质细胞和整个组织和单细胞的免疫组织化学形态学定量 RNA方法。在目标3中，我们将确定AD神经病理学对脓毒症的贡献程度- 导致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小鼠模型中的反应，以测试在存在CS的情况下对CS敏感性增加的潜力。 常见的AD神经病理学和基因变异。