Microglia-Amyloid interactions in delirium superimposed on dementia

摘要 普通外科手术后认知功能受损是一个日益关注的问题，特别是在5岁以上的人群中。 在美国，有100万人患有痴呆症，包括阿尔茨海默病（AD）， 需要手术修复的骨折风险增加3倍。骨科手术后，认知能力的急性变化 功能障碍，通常称为术后谵妄，发生在高达89%的既存痴呆患者中， 并且与预后较差相关，与未接受化疗的患者相比，1年死亡率的风险甚至高出2倍 痴呆或精神错乱我们的长期目标是确定手术引起的认知功能障碍的机制。 功能障碍，并提供安全有效的方法来减少这种潜在的破坏性并发症。 从R 01-AG 057525中，我们发现骨科手术会触发β淀粉样蛋白（A β）的急性沉积， 转基因阿尔茨海默氏症（CVN-AD）小鼠的大脑。这一建议继续描述了先天的作用， 常见骨科手术（胫骨骨折）后血脑屏障（BBB）的免疫失调 以及使用术后谵妄叠加痴呆模型的小胶质细胞活化。整体 目的是描述谵妄叠加痴呆的免疫异质性，并评估 微创经皮迷走神经刺激（pVNS）对小胶质细胞功能和A β的影响 AD样小鼠手术后的水平。我们的中心假设是，免疫细胞簇的失调和 纤维蛋白原升高可导致AD小鼠术后出现谵妄样行为，术后pVNS 减弱这种影响。这一假设是基于申请人实验室获得的初步数据， 将通过追求3个具体目标进行测试：1）开发谵妄小鼠大脑的单细胞图谱 2）分析术后小胶质细胞活化和A β沉积的机制 3）确定pVNS对BBB开放和小胶质细胞依赖性A β的影响。 手术后清除。这些模型和技术的可行性已经在申请人的申请中得到了证实。 手在这种创新的方法中，我们将采用功能转录组学与先进的计算 识别先天免疫单细胞景观对手术创伤和谵妄样反应的方法 痴呆小鼠大脑的变化。我们将继续描述神经免疫相互作用的特征， 使用动物模型以及器官芯片技术的血脑功能变化。我们还将测试 pVNS在促进术后A β清除和限制术后谵妄发作方面的有效性。的 拟议研究的理由是，成功完成将促进和扩大我们对 手术如何影响先天免疫系统，并将提供新的相关分子机制， 精神错乱神经退化和衰老这种知识非常重要，因为它有可能 解释手术如何影响脆弱的大脑，并确定新的目标，以防止术后谵妄。

ABSTRACT Impaired cognitive function after common surgical procedures is a growing concern especially among over 5 million people in the United States who suffer from dementia, including Alzheimer’s disease (AD), and thus have a 3-fold increased risk for fracture requiring surgical repair. After orthopedic surgery, acute changes in cognitive function, often referred to as postoperative delirium, occur in up to 89% of patients with preexisting dementia, and associate with poorer prognosis and even 2-fold greater risk for 1-year mortality compared to patients without dementia or delirium. Our long-term goal is to define the mechanisms that underlie surgery-induced cognitive dysfunction, and to provide safe and effective approaches to reduce this potentially devastating complication. From R01-AG057525 we discovered that orthopedic surgery triggers an acute deposition of amyloid-β (A) in the brains of transgenic Alzheimer’s (CVN‐AD) mice. This proposal continues to characterize the role of innate immune dysregulation following a common orthopedic surgery (tibial fracture) on the blood-brain barrier (BBB) and microglial activation using a model of postoperative delirium superimposed on dementia. The overall objectives are to characterize the immune heterogeneity of delirium superimposed on dementia, and to evaluate the efficacy of minimally-invasive percutaneous vagus nerve stimulation (pVNS) on microglial function and A levels in AD-like mice after surgery. Our central hypothesis is that dysregulation of immune cell clusters and elevated fibrinogen contribute to delirium-like behavior in AD mice after surgery, and that postoperative pVNS attenuates this effect. This hypothesis is based on preliminary data acquired in the applicants’ laboratories, and will be tested by pursuing 3 specific aims: 1) Develop a single-cell atlas of the mouse brain with delirium superimposed on dementia; 2) Analyze the mechanisms of microglial activation and A deposition after surgery in AD-like mice with delirium; and 3) Define the impact of pVNS on BBB opening and microglial-dependent A clearance after surgery. Feasibility for these models and techniques has been established in the applicants’ hands. In this innovative approach, we will employ functional transcriptomics with advanced computational approaches to identify the innate immune single-cell landscape in response to surgical trauma and delirium-like changes in the brain of dementia-prone mice. We will continue to characterize neuro-immune interactions and changes in blood-brain function using both animal models as well as organ-on-chip technology. We will also test the efficacy of pVNS to facilitate A clearance after surgery and limit the onset of postoperative delirium. The rationale for the proposed research is that successful completion will advance and expand our understanding of how surgery affects the innate immune system, and will provide new molecular mechanisms of relevance to delirium, neurodegeneration, and aging. Such knowledge is highly significant because it has the potential to explain how surgery impacts the vulnerable brain and identify novel targets to prevent postoperative delirium.