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

项目摘要/摘要 脓毒症幸存者患上新的慢性脑功能障碍的风险是后者的3倍，包括长期的认知和 情绪障碍，但败血症幸存者脑功能障碍的危险因素仍然知之甚少。淀粉样蛋白 60岁以上认知正常的人中有20%-50%存在贝塔(Aβ)病理，因此是一种常见的 即使在没有阿尔茨海默病诊断的败血症幸存者中，风险因素也是如此。 人类阿尔茨海默病和小鼠β病理增加大脑补体受体水平， 对先天免疫力至关重要。在细菌性败血症中，补体系统被强烈激活。因此，我们 假设脓毒症在β存在时驱动补体配体诱导补体增强 受体促进了小胶质细胞的激活和突触的丢失，增加了对新的大脑功能障碍的易感性。我们 将研究补体驱动的损伤和早期Aβ沉积在增强的脑功能障碍中的作用 败血症后存活的淀粉样变性小鼠模型(5xFAD小鼠)。具体来说，我们会： 目的1：确定脓毒症和症状前Aβ沉积是否增强补体介导 5xFAD脓毒症存活小鼠的神经炎症和突触丢失。我们假设慢性Aβ 补体受体C3aR的诱导和脓毒症诱导的C3表达导致小胶质细胞 激活，增加突触吞噬功能，减少突触传递。 目的2：确定脓毒症和症状前Aβ沉积是否增强补体介导的 5xFAD脓毒症存活小鼠的行为损害。我们假设空间记忆的缺陷， 背景歧视和动机在高水平任务中的损害程度低，并将决定 这些缺陷依赖于C3a受体抑制或诱导的C3缺失而产生的C3信号。 目的3：确定5xFAD败血症存活小鼠的突触吞噬功能是否依赖C3驱动 小胶质细胞激活。而另一些人则提出，小胶质细胞衰老有助于 神经退行性变，我们假设在脓毒症中小胶质细胞的激活导致Aβ增强的突触丢失。 利用一种新的微流控细胞培养平台，我们将确定C3a信号在阿尔茨海默氏症的背景下是否 小胶质细胞因子分泌增强和突触体吞噬功能增强是疾病神经病理学所必需的。 了解患有β的脓毒症幸存者的脑损伤机制将提供重要的 在未来针对补体激活的脑损伤预防试验中，为个性化策略奠定基础。

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.