Enhancement of Brain Dysfunction in Sepsis Survivors by Alzheimer’s Disease Neuropathology

阿尔茨海默病增强脓毒症幸存者的脑功能障碍

基本信息

批准号：
10338503
负责人：
Benjamin H Singer
金额：
$ 64.78万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2022-01-15 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10338503
关键词：
Acute Age Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Amyloid Amyloid beta-Protein Amyloidosis Animal Model Automobile Driving Bacteremia Behavioral Biological Markers Brain Brain Injuries C3AR1 gene Cell Culture Techniques Chemosensitization Chronic Cognition Disorders Cognitive Collection Complement Complement 3a Complement Activation Complement Receptor Critical Care Critical Illness Dependence Discrimination Functional disorder Future Hippocampus (Brain)Human Impaired cognition Impairment Individual Infection Injury Ligands Measures Mediating Microfluidics Microglia Modeling Mood Disorders Motivation Mus Natural Immunity Nerve Degeneration Nuclear Outcome Pathology Patients Peritoneal Phagocytosis Phenotype Population Problem Solving Receptor Inhibition Risk Risk Factors Role Sepsis Signal Transduction Survivors Synapses Synaptic Transmission Synaptosomes Syndrome United States abeta deposition amyloid pathology behavioral impairment brain dysfunction brain tissue comorbidity complement system cost cytokine functional decline functional disability glial activation improved injury prevention mouse model neuroinflammation neuropathology novel personalized strategies receptor senescence spatial memory survivorship systemic inflammatory response transcriptome

项目摘要

PROJECT SUMMARY/ABSTRACT Sepsis survivors carry over a 3-fold risk of new chronic brain dysfunction, including long-term cognitive and mood disorders, but risk factors for brain dysfunction in sepsis survivors remain poorly understood. Amyloid beta (Aβ) pathology is present in 20-50% of cognitively normal individuals over age 60 and is thus a common risk factor even in sepsis survivors without a preexisting Alzheimer’s disease diagnosis. Alzheimer’s disease in humans and Aβ pathology in mice increase brain levels of complement receptors which are critical to innate immunity. The complement system is strongly activated in bacterial sepsis. We therefore hypothesize that sepsis driven complement ligands in the presence of Aβ induced potentiation of complement receptors enhance microglial activation and synapse loss, increasing vulnerability to new brain dysfunction. We will examine the role of complement-driven injury and early Aβ deposition in enhanced brain dysfunction using a murine model of amyloidosis (5xFAD mice) which have survived sepsis. Specifically, we will: Aim 1: Determine if sepsis and presymptomatic Aβ deposition enhance complement-mediated neuroinflammation and synapse loss in 5xFAD sepsis survivor mice. We hypothesize that chronic Aβ induction of complement receptor C3aR combined with sepsis induced C3 expression results in microglial activation, increased synaptic phagocytosis, and reduced synaptic transmission. Aim 2: Determine if sepsis and presymptomatic Aβ deposition enhance complement-mediated behavioral impairment in 5xFAD sepsis survivor mice. We hypothesize that deficits in spatial memory, context discrimination, and motivation underly impairments in high level tasks and will determine the dependence of these deficits on C3 signaling through C3a receptor inhibition or inducible C3 deletion. Aim 3: Determine if synaptic phagocytosis in 5xFAD sepsis survivor mice is dependent on C3 driven microglial activation. While others have proposed that microglial senescence contributes to neurodegeneration, we hypothesize that microglial activation drives Aβ enhanced synapse loss in sepsis. Using a novel microfluidic cell culture platform, we will determine if C3a signaling in the setting of Alzheimer’s disease neuropathology is required for enhanced microglial cytokine secretion and synaptosome phagocytosis. Understanding mechanisms of brain injury in sepsis survivors with Aβ neuropathology will provide an important basis for personalized strategies in future trials of brain injury prevention directed at complement activation.

项目摘要/摘要败血症的生存具有新的慢性脑功能障碍的3倍风险，包括长期认知和情绪障碍，但败血症存活中脑功能障碍的危险因素仍然了解不足。淀粉样蛋白 Beta（Aβ）病理学以20-50％的认知正常人为60岁以上，因此是一种常见即使在败血症存活中，危险因素也没有先前存在的阿尔茨海默氏病诊断。小鼠的人类和Aβ病理学中的阿尔茨海默氏病增加了补体受体的水平对先天免疫至关重要。完成系统在败血症中被强烈激活。因此，我们假设在Aβ诱导的完成的情况下，败血症驱动配体驱动配体受体增强小胶质激活和突触丧失，增加了对新脑功能障碍的脆弱性。我们将检查补体驱动的损伤和早期Aβ沉积在增强脑功能障碍中的作用淀粉样变性的鼠模型（5xFAD小鼠）幸存于败血症。具体来说，我们将： AIM 1：确定败血症和PresymptomAβ沉积是否增强了补体介导的 5xFAD败血症生存小鼠的神经炎症和突触丧失。我们假设慢性Aβ 诱导诱导受体C3AR与败血症诱导的C3表达相结合导致小胶质细胞激活，突触吞噬作用增加以及突触传播减少。 AIM 2：确定败血症和PresymptomAβ沉积是否增强了补体介导的 5xFAD败血症生存小鼠的行为障碍。我们假设在空间内存中定义了这一点，上下文歧视和高级任务中损害的动力，并将确定这些依赖性通过C3A受体抑制或诱导的C3缺失定义了C3信号传导。 AIM 3：确定5xFAD败血症生存小鼠中的合成吞噬作用是否取决于C3驱动小胶质激活。而其他人则提出小胶质细胞感应有助于神经变性，我们假设小胶质细胞激活驱动Aβ增强败血症的突触丧失。使用新型的微流体细胞培养平台，我们将确定是否在阿尔茨海默氏症的情况下进行C3A信号传导疾病神经病理学是增强小胶质细胞因子分泌和突触体吞噬作用所必需的。了解患有Aβ神经病理学败血症生存中脑损伤的机制将提供重要的在未来的预防脑损伤预防试验中，针对完成激活的个性化策略的基础。