睡眠障碍、抑郁症和阿尔茨海默病 (AD) 被广泛报道为合并症。尽管小胶质细胞表型 M1 激活引发的神经炎症导致神经递质功能障碍和 Aβ 聚集，被认为是抑郁症和 AD 的主要原因，但亚慢性或慢性睡眠剥夺 (SD) 是否以及如何导致这些疾病的发生和发展尚不清楚。在两个 SD 中评估了记忆和抑郁样行为，然后通过 qRT-PCR、酶联免疫吸附测定昼夜节律标记、神经胶质细胞表型极化、细胞因子、抑郁相关神经递质和 AD 相关基因/蛋白表达进行测量。分别采用免疫吸附测定法、高效液相色谱法和蛋白质印迹法。两种 SD 均诱导放弃行为和快感缺乏，并增加昼夜节律标记周期昼夜节律调节器 2 (PER2) 表达，这在慢性 SD 中比亚慢性 SD 更严重而大脑和肌肉 ARNT 样蛋白 1 仅在慢性 SD 中减少。此外，在两种 SD 中均观察到小胶质细胞 M1 和星形胶质细胞 A1 表达以及促炎细胞因子、白细胞介素 (IL)-1β、IL-6 和肿瘤坏死因子-α 的增加，这在慢性 SD 中更为显着。同样，去甲肾上腺素和 5-羟色胺/5-羟基吲哚乙酸比率的降低更为显着，这对应于慢性 SD 中比亚慢性 SD 更严重的抑郁样行为。对于 AD，淀粉样前体蛋白 (APP) 和可溶性 (s)-APPβ 的增加以及 sAPPα 的减少在慢性病中更为显着。然而，sAPPα/sAPPβ 比率仅在慢性 SD 中下降。这些发现表明，这两种 SD 均通过增加 PER2 诱导抑郁样变化，导致神经炎症和神经递质功能障碍。然而，只有慢性 SD 才会引起记忆障碍，这可能是由于更严重的昼夜节律紊乱、更高的神经炎症和 APP 代谢失调所致。版权所有 © 2024。由 Elsevier B.V. 出版。

Sleep disorders, depression, and Alzheimer's disease (AD) are extensively reported as comorbidity. Although neuroinflammation triggered by microglial phenotype M1 activation, leading to neurotransmitter dysfunction and Aβ aggregation, is considered as the leading cause of depression and AD, whether and how sub-chronic or chronic sleep deprivation (SD) contribute to the onset and development of these diseases remains unclear.Memory and depression-like behaviors were evaluated in both SDs, and then circadian markers, glial cell phenotype polarization, cytokines, depression-related neurotransmitters, and AD-related gene/protein expressions were measured by qRT-PCR, enzyme-linked immunosorbent assay, high-performance liquid chromatography, and western-blotting respectively.Both SDs induced give-up behavior and anhedonia and increased circadian marker period circadian regulator 2 (PER2) expression, which were much worse in chronic than in the sub-chronic SD group, while brain and muscle ARNT-like protein-1 only decreased in the chronic-SD. Furthermore, increased microglial M1 and astrocyte A1 expression and proinflammatory cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α was observed in both SDs, which were more significant in chronic SD. Similarly, decreased norepinephrine and 5-hydroxytryptamine/5-hydroxyindoleacetic acid ratio were more significant, which corresponds to the worse depression-like behavior in chronic than sub-chronic-SD. With regard to AD, increased amyloid precursor protein (APP) and soluble (s)-APPβ and decreased sAPPα in both SDs were more significant in the chronic. However, sAPPα/sAPPβ ratio was only decreased in chronic SD.These findings suggest that both SDs induce depression-like changes by increasing PER2, leading to neuroinflammation and neurotransmitter dysfunction. However, only chronic SD induced memory impairment likely due to severer circadian disruption, higher neuroinflammation, and dysregulation of APP metabolism.Copyright © 2024. Published by Elsevier B.V.