Pathogenesis of Postoperative Cognitive Dysfunction

项目摘要/摘要。 术后认知功能障碍(POCD)，老年人最常见的术后并发症 患者是老年病学和老年学领域的一个重要研究领域，与 阿尔茨海默病(AD)痴呆症、发病率和死亡率以及护理成本的增加。然而， POCD的发病机制目前尚不清楚，这阻碍了对POCD的深入研究。与一致 血CX3CR1+单核细胞与线粒体通透性转移孔成分的关系 大脑中的亲环素D(CypD)调节神经炎症和线粒体功能，我们发表的工作 对小鼠的初步研究表明，CypD和CX3CR1+单核细胞介导的麻醉/手术- 以及感染引起的认知障碍。此外，阿尔茨海默病患者脑组织中CypD水平较高 转基因(TG)和老龄小鼠。因此，拟议的研究将评估麻醉/手术对 毒性，包括与AD神经发病机制相关的变化(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)相互作用 CX3CR1+单核细胞、沉淀因子和侮辱作用增加)和脑[衰老-或AD基因 突变相关的亲环素D升高(CypD，易感因素和门控调节)是必需的] 导致POCD。这项拟议研究的假设是麻醉/手术导致血液增加 CX3CR1+单核细胞与衰老和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。我们将使用化学和遗传技术 通过神经免疫学和行为学方法来实现三个具体目标的工具：(1)我们将 评估麻醉/手术对血CX3CR1+单核细胞和细胞因子水平的影响；脑- 浸润性CX3CR1+单核细胞、神经炎症、线粒体功能障碍、神经元功能障碍 行为；(2)我们将使用Cx3cr1Creer/+；R26iDTR/+和CypD基因敲除嵌合小鼠，在其中CX3CR1+ 单核细胞、小胶质细胞和CypD被耗尽，因此我们可以评估血液中CX3CR1+单核细胞和 脑组织CypD对麻醉/手术诱导的变化；(3)我们将测定一种单克隆化效果 CX3CR1配体CX3CL1的抗体；线粒体保护剂(WS635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)小鼠随年龄变化 匹配AD TG和老年(18个月大)小鼠(CypD水平较高)，同时使用体内细胞 耗竭、体内双光子钙成像、Western印迹、ELISA法、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一个未被充分研究的主题 新的假设，最终将为AD和老年患者提供更好的术后结果， 导致制定预防阿尔茨海默病的战略。

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.