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

项目概要/摘要 脓毒症幸存者患新的慢性脑功能障碍的风险超过3倍，包括长期认知和 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 β（Aβ）病理存在于20-50%的60岁以上认知正常个体中，因此是常见的 即使在没有预先存在的阿尔茨海默病诊断的败血症幸存者中也是危险因素。 人类的阿尔茨海默病和小鼠的Aβ病理学增加了脑中补体受体的水平， 对先天免疫至关重要补体系统在细菌性脓毒症中被强烈激活。因此我们 假设脓毒症在Aβ诱导补体增强情况下驱动补体配体 受体增强小胶质细胞活化和突触损失，增加对新的脑功能障碍的脆弱性。我们 将研究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），其在脓毒症中存活。具体而言，我们将： 目的1：确定脓毒症和症状前Aβ沉积是否增强补体介导的 在5xFAD脓毒症存活小鼠中的神经炎症和突触损失。我们假设慢性Aβ 诱导补体受体C3 aR结合脓毒症诱导的C3表达导致小胶质细胞 激活，增加突触吞噬作用和减少突触传递。 目的2：确定脓毒症和症状前Aβ沉积是否增强补体介导的 在5xFAD脓毒症存活小鼠中的行为损害。我们假设空间记忆的缺陷， 背景歧视和动机是高水平任务障碍的基础，并将决定 这些缺陷依赖于通过C3 a受体抑制或诱导性C3缺失的C3信号传导。 目的3：确定5xFAD脓毒症存活小鼠中的突触吞噬作用是否依赖于C3驱动 小胶质细胞激活。虽然其他人提出小胶质细胞衰老有助于 因此，我们假设脓毒症中小胶质细胞活化驱动Aβ增强的突触丢失。 使用一种新的微流控细胞培养平台，我们将确定在阿尔茨海默氏症的背景下，C3 a信号传导是否 疾病神经病理学是增强的小胶质细胞因子分泌和突触体吞噬作用所必需的。 了解脓毒症幸存者Aβ神经病理学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的个性化策略的基础。

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.