Orexin双受体拮抗剂Suvorexant在睡眠-觉醒紊乱及阿尔茨海默病进程中的作用机制研究

睡眠-觉醒紊乱（SWD）是阿尔茨海默病（AD）的早期症状，也是促进AD进展的严重临床问题，但其发生发展机制不清。我们前期研究发现5×FAD转基因小鼠出现睡眠片段化，觉醒次数及时间增加，NREM及REM期所占比例减少，Orexin神经元数目增多且在皮层及外侧下丘脑与β-淀粉样蛋白（Aβ）共定位，海马及外侧下丘脑小胶质细胞数量增多，认知及执行功能受损。为此我们提出科学假设：Orexin双受体拮抗剂可能通过抑制小胶质细胞从而对SWD及认知行为损伤产生改善作用。本课题拟在此基础上，在动物和细胞水平研究Orexin不断增加Aβ，使小胶质细胞COX2过度激活，产生神经炎症因子，进而影响睡眠觉醒，加速AD进程的机制。寻找AD的早期干预靶点，探索其神经炎症的分子机制，对揭示Orexin、大脑皮层Aβ、神经炎症、昼夜节律改变和AD进程相关的规律具有重要意义，为揭示发病机制和潜在的治疗靶点提供新的线索。

Sleep-wake disturbance (SWD) is an early symptom of Alzheimer's disease (AD) and a serious clinical problem that promotes the progression of AD, but its mechanism of occurrence and development is unclear. Our previous study found that 5×FAD transgenic mice had fragmented sleep, increased frequencies and longer time of arousal, decreased proportion of NREM and REM phases, increased number of Orexin neurons, and increased levels of β-amyloid (Aβ) in the cortex and lateral hypothalamus, increased numbers of microglia in the hippocampus and lateral hypothalamus, and impaired cognitive and executive function. Therefore, we put forward a scientific hypothesis: Orexin dual receptor antagonists may improve SWD and cognitive behavioral impairment by inhibiting microglia. On this basis, this project intends to study the mechanism by which Orexin continuously increases Aβ at the animal and cell levels, which causes the over-activation of COX2 in microglia, and produces neuroinflammatory factors, which in turn affect sleep arousal and accelerate the process of AD. Finding the early intervention targets of AD and exploring the molecular mechanism of its neuroinflammation are of great significance for revealing the laws related to SWD, Orexin, cerebral cortex Aβ, neuroinflammation, circadian rhythm changes and AD process; and provide new clues to reveal the pathogenesis and potential therapeutic targets.