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.
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Data Availability
The data that support the funding of this study are available from the corresponding author upon reasonable request.
Abbreviations
- AD:
-
Alzheimer’s disease
- AZ:
-
Active zone
- CD33:
-
Siglec-3
- CFH:
-
Regulatory complement factor H
- CON:
-
Control
- CSR:
-
Chronic sleep restriction
- DAM:
-
Disease-associated microglia
- GM1:
-
Monosialo-ganglioside 1
- NOR:
-
Novel objective recognition
- PSD95:
-
Postsynaptic protein 95
- ROI:
-
Polygonal region of interest
- SC:
-
Synaptic cleft
- SHP-1/2:
-
Tyrosine phosphatase-1/2
- siRNA:
-
Small interfering RNA
- Syk:
-
Spleen tyrosine kinase
- SYP:
-
Synaptophysin
- TREM2:
-
Triggering receptor expressed on myeloid cells 2
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Acknowledgements
We would also like to acknowledge the support of Yan Li and Ying Zhang on this project who shared equipment and experimental techniques.
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This work was supported by funds from the National Natural Science Foundation of China (Grant Nos. 81901237, 81774113, 81974540), Beijing, China.
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ST, QW, and QZ conceived and designed this study. ST, HG, and JS performed the experiments, and ST and QZ drafted the manuscript. NL and YZ conducted data analysis, and LY and MW helped to revise the manuscript. And all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Tan, S., Gao, H., Sun, J. et al. CD33/TREM2 Signaling Mediates Sleep Deprivation-Induced Memory Impairment by Regulating Microglial Phagocytosis. Neuromol Med 25, 255–271 (2023). https://doi.org/10.1007/s12017-023-08733-6
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DOI: https://doi.org/10.1007/s12017-023-08733-6