General Anesthesia and Alzheimer's Disease Neuropathogenesis

描述（由申请人提供）：一些研究表明，阿尔茨海默病（AD）是最常见的痴呆症之一，麻醉和手术可能会促进这种疾病的发生。我们最近的研究表明，常用的吸入麻醉剂异氟醚可以诱导caspase激活和凋亡，从而增加淀粉样蛋白2 （A2）的生成，A2是AD患者老年斑的关键成分。这些发现可能具有潜在的临床重要性，因为麻醉增加A2生成和细胞凋亡可能会触发或加剧AD的发展。然而，异氟醚诱导细胞凋亡和A2生成（凋亡/A2生成）的上游潜在机制和下游后果在很大程度上仍然未知。与过量钙可触发或促成细胞凋亡和异氟醚可影响突触功能的观点一致，我们的初步研究表明，异氟醚可以1)诱导凋亡/A2生成，2)提高胞质钙水平，3)降低皮层神经元表面NMDA受体。因此，我们的主要假设是异氟醚提高细胞质钙水平，诱导细胞凋亡/A2生成，导致突触NMDA受体内吞。我们将通过体外和体内方法使用化学和遗传学工具来实现三个特定目标：1)表征异氟烷对细胞凋亡/A2生成的影响；2)确定胞质钙水平的改变是否与异氟醚诱导的细胞凋亡/A2生成有关；3)确定异氟醚对突触NMDA受体内吞作用的影响。本研究旨在扩展我们最近关于异氟醚诱导细胞凋亡/A2生成的发现，以进一步确定其潜在机制及其对突触NMDA受体内吞作用的影响。本项目所产生的数据将为异氟醚诱导细胞凋亡/A2生成的机制及其对NMDA受体介导的突触功能损害的贡献提供新的信息。这项研究的结果可能最终指导研究人员和临床医生设计更安全的麻醉剂，并为患者，特别是老年和AD患者提供更好的麻醉护理。公共卫生相关性：我们最近的研究表明，麻醉异氟醚可诱导细胞凋亡并增加淀粉样蛋白2 （A2）的生成。在拟议的研究中，我们将进一步描述这些影响，并确定其上游机制和下游后果。

DESCRIPTION (provided by applicant): Several studies have suggested that Alzheimer's disease (AD), one of the most common forms of dementia, might be facilitated by anesthesia and surgery. Our recent research showed that the commonly used inhalational anesthetic isoflurane could induce caspase activation and apoptosis, which in turn increases generation of amyloid 2-protein (A2), the key component of senile plaques in AD patients. These findings could have potential clinical importance since increased A2 generation and apoptosis by anesthesia could conceivably serve to trigger or exacerbate the development of AD. However, the up-stream underlying mechanisms and the down-stream consequences of the isoflurane- induced apoptosis and A2 generation (apoptosis/A2 generation) remain largely unknown. Consistent with the notions that excessive calcium can trigger or contribute to apoptosis and isoflurane can affect synaptic function, our preliminary studies have shown that isoflurane can 1) induce apoptosis/A2 generation, 2) enhance cytosolic calcium levels, and 3) reduce surface NMDA receptors in cortical neurons of naove mice. Thus, our main hypothesis is that isoflurane enhances cytosolic calcium levels to induce apoptosis/A2 generation, leading to synaptic NMDA receptor endocytosis. We will employ chemical and genetic tools through both in vitro and in vivo approaches to accomplish three Specific Aims: 1) to characterize effects of isoflurane on apoptosis/A2 generation; 2) to define whether the alterations in cytosolic calcium levels are associated with isoflurane-induced apoptosis/A2 generation; and 3) to determine the effects of isoflurane on synaptic NMDA receptor endocytosis. The proposed research aims to extend our recent findings that isoflurane induces apoptosis/A2 generation to further determine the underlying mechanisms and their effects on synaptic NMDA receptor endocytosis. The data generated in this project would provide novel information regarding the mechanisms of isoflurane- induced apoptosis/A2 generation and their contribution to the impairment of NMDA receptor-mediated synaptic function. The results of this study may ultimately guide researchers and clinicians to design safer anesthetics and to provide better anesthesia care for patients, particularly senior and AD patients. PUBLIC HEALTH RELEVANCE: Our recent research showed that anesthetic isoflurane induces apoptosis and increases the generation of amyloid-2 protein (A2). In the proposed research we will further characterize these effects and determine their up-stream mechanisms and down-stream consequences.