Pathogenesis of Postoperative Cognitive Dysfunction

项目概要/摘要。 术后认知功能障碍（POCD）是老年人最常见的术后并发症， 患者和一个重要的研究领域，在老年医学和老龄化领域， 增加阿尔茨海默病（AD）痴呆、发病率和死亡率以及护理成本。但 POCD的发病机制尚不清楚，阻碍了对POCD的深入研究。符合 血液CX 3CR 1+单核细胞和线粒体渗透性转换孔组分 亲环素D（CypD）在大脑中调节神经炎症和线粒体功能，我们发表的工作 在小鼠中的初步研究表明，CypD和CX 3CR 1+单核细胞介导的麻醉/手术- 和感染引起的认知障碍此外，CypD水平在AD的脑组织中更高， 转基因（Tg）和老年小鼠。因此，拟议的研究将评估麻醉/手术对 毒性，包括AD神经发病相关的变化（例如，CypD水平升高， 神经炎症、线粒体功能障碍和神经元功能障碍）。此外，我们将定义一个 POCD发病机制的多因素模型，其中血液（麻醉/手术诱导） 增加CX 3CR 1+单核细胞，沉淀因子和侮辱行动）和大脑[老化-或AD基因 需要亲环素D（CypD）突变相关升高，诱发因素和门控调节 导致POCD拟议研究的假设是，麻醉/手术引起的血液中 CX 3CR 1+单核细胞在功能上与衰老和AD基因突变相关的脑功能增强相互作用 CypD，导致小鼠神经元功能障碍和POCD样行为。我们将使用化学和基因 通过神经免疫学和行为学方法来实现三个具体目标：（1）我们将 评估麻醉/手术对血液CX 3CR 1+单核细胞和细胞因子水平的影响; 浸润性CX 3CR 1+单核细胞、神经炎症、线粒体功能障碍、神经元功能障碍，以及 （2）我们将使用Cx 3cr 1CreER/+; R26 iDTR/+和CypD敲除嵌合小鼠，其中CX 3CR 1 + 单核细胞、小胶质细胞和CypD被耗尽，因此我们可以评估血液CX 3CR 1+单核细胞的作用， 脑CypD对麻醉/手术引起的变化;（3）我们将确定单克隆抗体的作用 CX 3CR 1配体CX 3CL 1的抗体;以及线粒体上的线粒体保护剂（WS 635和维生素K2）。 麻醉/手术引起的变化。我们将包括野生型和成年（4个月大）小鼠与年龄 匹配的AD Tg和老年（18个月大）小鼠（具有较高水平的CypD），同时采用体内细胞 消耗，体内双光子钙成像，Western印迹，ELISA，免疫组织化学，流式细胞术， 和行为测试该提案旨在通过测试来研究创新系统中的一个未充分研究的主题 新的假设，这将最终为AD和老年患者提供更好的术后结局， 从而制定预防AD的策略。

Project Summary/Abstract. Postoperative cognitive dysfunction (POCD), the most common postoperative complication among geriatric patients and an important research area in the field of Geriatrics and Aging, is associated with substantially increased Alzheimer’s disease (AD) dementia, morbidity, and mortality as well as cost of care. However, the pathogenesis of POCD is still largely unknown, which impede the further studies into POCD. Consistent with the notion that blood CX3CR1+ monocytes and the mitochondria permeability transition pore component Cyclophilin D (CypD) in the brain regulate neuroinflammation and mitochondrial function, our published work and preliminary studies in mice showed that CypD and CX3CR1+ monocytes mediated anesthesia/surgery- and infection-induced cognitive impairment. In addition, CypD levels are higher in brain tissues of AD transgenic (Tg) and aged mice. Thus, the proposed research will assess the effects of anesthesia/surgery on toxicity, including the AD neuropathogenesis-associated changes (e.g., increased CypD levels, neuroinflammation, mitochondrial dysfunction, and neuronal dysfunction). Moreover, we will define a multifactorial model of POCD pathogenesis where the interaction of blood (anesthesia/surgery-induced increases in CX3CR1+ monocytes, the precipitating factor and insulting action) and brain [aging- or AD gene mutation-associated elevation of Cyclophilin D (CypD), the predisposing factor and gating regulation] is needed to cause POCD. The hypothesis of the proposed study is that anesthesia/surgery-induced increases in blood CX3CR1+ monocytes functionally interact with aging- and AD gene mutation-associated enhancement of brain CypD, leading to neuronal dysfunction and POCD-like behavior in mice. We will employ chemical and genetic tools through both neuroimmunology and behavioral approaches to accomplish three Specific Aims: (1) we will assess the effects of anesthesia/surgery on levels of blood CX3CR1+ monocytes and cytokines; brain- infiltrating CX3CR1+ monocytes, neuroinflammation, mitochondrial dysfunction, neuronal dysfunction, and behavior; (2) we will use Cx3cr1CreER/+;R26iDTR/+ and CypD knockout chimeric mice in which CX3CR1+ monocytes, microglia and CypD are depleted so we can assess the roles of blood CX3CR1+ monocytes and brain CypD on the anesthesia/surgery-induced changes; (3) we will determine the effects of a monoclonal antibody for the CX3CR1 ligand CX3CL1; and the protectors of mitochondria (WS635 and Vitamin K2) on the anesthesia/surgery-induced changes. We will include wild-type and adult (4 month-old) mice versus age matched AD Tg and aged (18 month-old) mice (with higher levels of CypD) while employing in vivo cell depletion, in vivo two-photon calcium imaging, Western blot, ELISA, immunohistochemistry, flow cytometry, and behavioral tests. This proposal aims to investigate an understudied topic in innovative systems by testing novel hypotheses, which would ultimately provide better postoperative outcomes for AD and geriatric patients, leading to the development of strategies to prevent AD.