Up-regulated Ganglioside GD3 in microglia following global cerebral ischemia promote the delayed hippocampal neuronal loss
Jing Wang1, Robert K Yu1, Krishnan Dhandapani2 and Darrell Brann1 1Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912; 2Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912
Stroke leads to long-term disabilities in human, spanning from psychological behavioral changes to physical paralysis and death. From all stroke types, about 80% is ischemic and not always fatal. Global cerebral ischemia in rodents is a widely used stroke model to simulate human ischemic stroke during cardiac arrest, shock, and asphyxia. The well-known pathology of GCI in both animals and human is characterized by a delayed loss of neuronal cells (3-7 day after ischemia), and progressive accumulation of glial scar in the CA1 region of hippocampus. Various cell death pathways have been invoked to explain the molecular mechanisms underlying the selective hippocampal neuronal cell death following GCI, including excitotoxicity, oxidative stress, and apoptosis-dependent mechanisms. However, the potential role of microglial phagocytosis-induced neuronal loss is poorly recognized and has not been well studied. Here, we present data showing that the b-series gangliosides GD3-synthase gene is upregulated the hippocampal tissue from day 2 to day 7 following GCI. Confocal microscopy revealed that the up-regulated ganglioside GD3 is predominantly co-localized with microglial marker CD11b, but not with astrocyte marker GLAST1. This histological finding is confirmed by Western blot on lysate from dissociated brain cells, which revealed that GD3-synthase up-regulation was mainly detected in the CD11b-positive microglial cells from 1~4day post injury, but not in the CD11b-negative astrocyte portion. To investigate the potential role of ganglioside GD3 in microglia after ischemic stroke, we compared the microglia activation and neuronal loss in WT and GD3 synthase knock-out (GD3S-KO) mice following GCI. Results showed increased neuronal survival at 4-7 day post injury in the hippocampal CA1 of GD3S-KO mice, as compared with WT controls, indicating that GD3 may promote delayed neuronal cell death after GCI. Moreover, this difference between GD3S-KO versus WT is not due to an altered inflammatory response of microglia, but rather from a decrease in the phagocytosis of neurons by microglia that occurs in response to the ischemic injury. This study provides the first evidence that ganglioside GD3 regulates the functional reaction of microglia in an ischemic stroke model. Our data also suggest that targeting ganglioside-associated phagocytosis of microglia might be a novel therapeutic strategy in the attempt to protect neurons from delayed death following ischemic brain injury.
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