CD33/TREM2 Signaling Mediates Sleep Deprivation-Induced Memory Impairment by Regulating Microglial Phagocytosis
Shuwen Tan1, Hui Gao1, Jianyu Sun1
1Department of Anesthesiology and Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
Abstract:
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.
Insights
Chronic sleep restriction impairs memory by altering microglial function. Activating CD33 and inhibiting TREM2 may offer therapies for sleep loss-induced memory deficits.
Area of Science:
- Neuroscience
- Immunology
- Sleep Research
Background:
- Sleep deprivation significantly impairs memory in adults.
- Microglia-mediated synaptic elimination is crucial in sleep deprivation.
- The CD33/TREM2 pathway's role in sleep loss-related memory decline is unexplored.
Purpose of the Study:
- To investigate the CD33/TREM2 signaling pathway's role in memory impairment during chronic sleep restriction (CSR).
- To evaluate the therapeutic potential of modulating this pathway for sleep loss-induced memory deficits.
Main Methods:
- Adult male C57BL/6 mice underwent 7 days of daily 20-hour sleep restriction.
- Memory was assessed using Y-maze and novel object recognition tests.
- Hippocampal CD33 and TREM2 protein levels were analyzed; microglial phagocytosis was evaluated in BV2 cells.
- Monosialo-ganglioside 1 (GM1) was administered to assess its effect on the CD33/TREM2 pathway and memory.
Main Results:
- Sleep-restricted mice showed significant memory deficits and increased microglial phagocytosis.
- CSR led to decreased CD33 and increased TREM2 protein levels in the hippocampus.
- GM1 administration activated CD33, inhibited TREM2-mediated phagocytosis, and reversed memory impairment and synaptic loss.
Conclusions:
- The CD33/TREM2 signaling pathway is implicated in sleep deprivation-induced memory deficits.
- Modulating microglial phagocytosis via CD33 activation or TREM2 inhibition offers potential therapeutic strategies for memory loss due to sleep deprivation.
