1. Ganglioside GD3 is up‐regulated in microglia and regulates phagocytosis following global cerebral ischemia
- Author
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Yan Dong, Jing Wang, Yujiao Lu, Quanguang Zhang, Krishnan M. Dhandapani, Robert K. Yu, and Darrell W. Brann
- Subjects
Male ,Phagocytosis ,Ischemia ,Hippocampal formation ,Biochemistry ,Phagolysosome ,Article ,Brain Ischemia ,Mice ,Cellular and Molecular Neuroscience ,Gangliosides ,medicine ,Animals ,Ganglioside GD3 ,Mice, Knockout ,Neurons ,Microglia ,Chemistry ,medicine.disease ,Coculture Techniques ,Up-Regulation ,Astrogliosis ,Cell biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,nervous system ,Neuron - Abstract
Gangliosides, the major sialic-acid containing glycosphingolipids in the mammalian brain, play important roles in brain development and neural functions. Here, we show that the b-series ganglioside GD3 and its biosynthetic enzyme, GD3-synthase (GD3S), were up-regulated predominantly in the microglia of mouse hippocampus from 2 to 7 days following global cerebral ischemia (GCI). Interestingly, GD3S knockout (GD3S-KO) mice exhibited decreased hippocampal neuronal loss following GCI, as compared to wild-type (WT) mice. While comparable levels of astrogliosis and microglial proliferation were observed between WT and GD3S-KO mice, the phagocytic capacity of the GD3S-KO microglia was significantly compromised after GCI. At 2 and 4 days following GCI, the GD3S-KO microglia demonstrated decreased amoebic morphology, reduced neuronal material engulfment, and lower expression of the phagolysosome marker CD68, as compared to the WT microglia. Finally, by using a microglia-primary neuron co-culture model, we demonstrated that the GD3S-KO microglia isolated from mouse brains at 2 days after GCI are less neurotoxic to co-cultured hippocampal neurons than the WT-GCI microglia. Moreover, the percentage of microglia with engulfed neuronal elements in the co-cultured wells was also significantly decreased in the GD3S-KO mice after GCI. Interestingly, the impaired phagocytic capacity of GD3S-KO microglia could be partially restored by pre-treatment with exogenous ganglioside GD3. Altogether, this study provides functional evidence that ganglioside GD3 regulates phagocytosis by microglia in an ischemic stroke model. Our data also suggest that the GD3-linked microglial phagocytosis may contribute to the mechanism of delayed neuronal death following ischemic brain injury.
- Published
- 2021