Department of Anesthesiology and Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China.
Neuromolecular Med. 2023 Jun;25(2):255-271. doi: 10.1007/s12017-023-08733-6. Epub 2023 Jan 14.
Sleep deprivation causes significant memory impairment in healthy adults. Extensive research has focused on identifying the biological mechanisms underlying memory impairment. Microglia-mediated synaptic elimination plays an indispensable role in sleep deprivation. Here, the potential role of the CD33/TREM2 signaling pathway in modulating memory decline during chronic sleep restriction (CSR) was evaluated. In this study, adult male C57BL/6 mice were sleep-restricted using an automated sleep deprivation apparatus for 20 h per day for 7 days. The Y-maze test revealed that spontaneous alternation was significantly reduced in CSR mice compared with control mice. The percentage of exploratory preference for the novel object in CSR mice was significantly decreased compared with that in control mice. These memory deficits correlated with aberrant microglial activation and increased phagocytic ability. Moreover, in CSR mice, the CD33 protein level in hippocampal tissue was significantly downregulated, but the TREM2 protein level was increased. In BV2 microglial cells, downregulation of CD33 increased TREM2 expression and improved microglial phagocytosis. Then, the sialic ligand monosialo-ganglioside 1 (GM1, 20 mg/kg, i.p.) was administered to mice once a day during CSR. Our results further showed that GM1 activated CD33 and consequently disturbed TREM2-mediated microglial phagocytosis. Finally, GM1 reversed CSR-induced synaptic loss and memory impairment via the CD33/TREM2 signaling pathway in the CA1 region of the hippocampus. This study provides novel evidence that activating CD33 and/or inhibiting TREM2 activity represent potential therapies for sleep loss-induced memory deficits through the modulation of microglial phagocytosis.
睡眠剥夺会导致健康成年人的记忆力显著受损。大量研究集中在确定导致记忆力受损的生物学机制上。小胶质细胞介导的突触消除在睡眠剥夺中起着不可或缺的作用。在这里，评估了 CD33/TREM2 信号通路在调节慢性睡眠限制 (CSR) 期间记忆下降中的潜在作用。在这项研究中，成年雄性 C57BL/6 小鼠使用自动睡眠剥夺装置每天剥夺 20 小时，持续 7 天。Y 迷宫测试显示，与对照组相比，CSR 小鼠的自发交替明显减少。与对照组相比，CSR 小鼠对新物体的探索偏好百分比显著降低。这些记忆缺陷与异常小胶质细胞激活和吞噬能力增加有关。此外，在 CSR 小鼠中，海马组织中的 CD33 蛋白水平显著下调，而 TREM2 蛋白水平增加。在 BV2 小胶质细胞中，下调 CD33 增加了 TREM2 的表达并改善了小胶质细胞的吞噬作用。然后，在 CSR 期间，每天给小鼠腹腔内注射一次唾液酸配基单唾液酸神经节苷脂 1（GM1，20mg/kg）。我们的结果进一步表明，GM1 激活了 CD33，从而干扰了 TREM2 介导的小胶质细胞吞噬作用。最后，GM1 通过 CA1 区的 CD33/TREM2 信号通路逆转了 CSR 诱导的突触丢失和记忆障碍。这项研究提供了新的证据，即通过调节小胶质细胞吞噬作用，激活 CD33 和/或抑制 TREM2 活性可能成为治疗睡眠剥夺引起的记忆缺陷的潜在疗法。
