Ganglioside GD3 is up‐regulated in microglia and regulates phagocytosis following global cerebral ischemia. Issue 3 (7th July 2021)

• Record Type: Journal Article
• Authors: Wang, Jing; Zhang, Quanguang; Lu, Yujiao; Dong, Yan; Dhandapani, Krishnan M.; Brann, Darrell W.; Yu, Robert K.
• Is Part Of: Journal of neurochemistry. Volume 158:Issue 3(2021)
• Page Start: 737
• Page End: 752
• Publication Date: 2021-07-07
• Subjects: Ganglioside GD3 -- GD3‐synthase -- global cerebral ischemia -- microglia -- phagocytosis -- stroke; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15455
• Languages: English
• ISSNs: 0022-3042

Abstract

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. Abstract : We found that ganglioside GD3 expression can be up‐regulated in microglia in the mouse brain after global cerebral ischemia. We also detected an increased neuronal survival, and decreased microglia phagocytosis in the hippocampal region of the GD3 synthase‐knockout (GD3S‐KO) mice compared to the WT after brain ischemia. We proposed that the up‐regulated GD3 enhanced the phagocytic capacity of microglia, which may contribute to the mechanism of delayed neuronal death following ischemic brain injury.