Cognitive impairments and circadian rhythm disorders are the main clinical manifestations of Alzheimer's disease (AD). Orexin has been reported as abnormally elevated in the cerebrospinal fluid of AD patients, accompanied with cognitive impairments. Our recent research revealed that suvorexant, a dual orexin receptor antagonist, could improve behavioral circadian rhythm disorders in 9-month-old APP/PS1 mice. Here we further observed whether suvorexant could ameliorate the cognitive decline in APP/PS1 mice by using behavioral tests, and investigated the possible mechanisms by in vivo electrophysiological recording, western blot, and immunochemistry. The results showed that suvorexant treatment effectively ameliorated the cognitive impairments, alleviated in vivo hippocampal long-term potentiation suppression, restored the circadian phosphorylated CREB expression in the hippocampus, and reduced amyloid-β protein deposition in the hippocampus and cortex in APP/PS1 mice. These results indicate that the neuroprotective effects of suvorexant against AD are involved in the reduction of amyloid-β plaques, improvement of synaptic plasticity, and circadian expression of phosphorylated CREB, suggesting that suvorexant could be beneficial to the prevention and treatment of AD.

中文翻译：

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Suvorexant 改善 APP/PS1 转基因小鼠的认知障碍和病理

认知障碍和昼夜节律紊乱是阿尔茨海默病 (AD) 的主要临床表现。据报道，在 AD 患者的脑脊液中，食欲素异常升高，并伴有认知障碍。我们最近的研究表明，suvorexant 是一种双食欲素受体拮抗剂，可以改善 9 个月大的 APP/PS1 小鼠的行为昼夜节律紊乱。在这里，我们通过行为测试进一步观察 suvorexant 是否可以改善 APP/PS1 小鼠的认知能力下降，并通过体内电生理记录、蛋白质印迹和免疫化学研究可能的机制。结果表明，suvorexant治疗有效改善认知障碍，缓解体内海马长时程增强抑制，恢复海马中昼夜节律磷酸化的 CREB ​​表达，并减少 APP/PS1 小鼠海马和皮层中淀粉样蛋白-β 蛋白的沉积。这些结果表明，suvorexant 对 AD 的神经保护作用涉及减少淀粉样蛋白斑块、改善突触可塑性和磷酸化 CREB ​​的昼夜节律表达，表明 suvorexant 可能有益于 AD 的预防和治疗。