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

基本信息

批准号：
10525755
负责人：
Julie Anne Bastarache
金额：
$ 194.06万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10525755
关键词：
Acute Address Affect Age Alzheimer&apos s disease model Alzheimer&apos s disease related dementia American Animal Model Animals Apoptosis Astrocytes Attention Behavior Behavior assessment Behavioral Biological Markers Blood Coagulation Disorders Brain Brain Injuries Cecum 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 (Brain)Immune Immunohistochemistry Impaired cognition Impairment Individual Infection Inflammation Inflammatory Inflammatory Response Injections Injury Intensive Care Units Intervention Studies Learning Length of Stay Ligation 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 Pharmacology Phase Physiological 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 abeta deposition aged aging brain behavior measurement behavioral outcome brain cell brain dysfunction care costs clinically relevant disability emotion regulation emotional functioning falls genetic variant human old age (65+)in vivo intraperitoneal juvenile animal mixed dementia mortality mouse model neuroinflammation neuromuscular neuropathology pathogen polymicrobial sepsis protein expression response septic septic patients sex sustained attention synaptic pruning systemic inflammatory response tau Proteins young adult

Acute Address Affect Age Alzheimer&apos s disease model Alzheimer&apos s disease related dementia American Animal Model Animals Apoptosis Astrocytes Attention Behavior Behavior assessment Behavioral Biological Markers Blood Coagulation Disorders Brain Brain Injuries Cecum 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 (Brain)Immune Immunohistochemistry Impaired cognition Impairment Individual Infection Inflammation Inflammatory Inflammatory Response Injections Injury Intensive Care Units Intervention Studies Learning Length of Stay Ligation 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 Pharmacology Phase Physiological 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 abeta deposition aged aging brain behavior measurement behavioral outcome brain cell brain dysfunction care costs clinically relevant disability emotion regulation emotional functioning falls genetic variant human old age (65+)in vivo intraperitoneal juvenile animal mixed dementia mortality mouse model neuroinflammation neuromuscular neuropathology pathogen polymicrobial sepsis protein expression response septic septic patients sex sustained attention synaptic pruning systemic inflammatory response tau Proteins young adult

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项目摘要

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.

抽象的败血症在老年人中的较高患病率也与多种类型的诊断率提高有关痴呆症包括阿尔茨海默氏病和相关痴呆症（ADRD）。慢性障碍包括变化在记忆和注意力中，情绪功能和神经肌肉力量都对患者和家庭。这种持续损害的确切机制未知，但数据支持角色感染后长期活化的小胶质细胞。在这一关键期间对神经学变化的理解缺乏适当的动物模型和简短的实验终点会阻碍时间段。行为评估可能会因低血统的妄想状态和疾病行为而严重混淆，许多评估已经在年轻动物而不是老年动物中进行了研究，没有其他相关的AD神经病理学进一步限制解释性和预测能力。我们将解决这些挑战中的每一个，并测试总体假设，即年龄和AD神经病理学易感大脑的总体假设为了更大的神经元损害，长时间的小胶质细胞激活和较差的认知结果败血症。此外，我们假设老年人的小胶质细胞具有更强的炎症反应以及下调感染的能力降低导致持续认知障碍的能力，特别是在存在其他与广告相关的神经病理学的情况下。我们的三个目标将在年轻成人（3个月）和老年小鼠（长达18个月），体内数据将由Ex Vivo支持电生理学，免疫组织化学和分子生物学方法。我们将评估我们的关键结果从疾病中康复后长达90天。在AIM 1中，我们将证明风险增加的程度老年败血症后，持续的认知障碍和长期神经炎症给年轻动物。我们将使用Cecal浆液注射来使用啮齿动物长达18个月的小鼠诱导败血症概括急性脑功能障碍的主要定义特征的模型，包括：急性神经炎症反应，脑电图的破坏，行为范围定义了一系列认知和神经肌肉结构域和海马长期潜力受损。在AIM 2中，我们将直接检查小胶质细胞使用临床相关的败血症后持续认知障碍的作用生物标志物，小胶质细胞和整个组织和单细胞的免疫组织化学形态定量 RNA接近。在AIM 3中，我们将确定AD神经病理学有助于败血症的程度诱导认知障碍和脑功能障碍。我们将比较行为结果和小胶质在两个不同的AD小鼠模型中的响应，以测试在存在下对CS敏感性提高的潜力常见的AD神经病理学和基因变异。