Abstract WP115: Netrin-1 Promotes Oligodendrogenesis After Experimental Stroke

Abstract

Introduction: oligodendrocyte injury after ischemic stroke influences the integrity of white matter, which ultimately leads to neurological deficits. Netrin-1 (NT-1) plays a crucial role in axon guidance during neural development. Also, it promotes oligodendrocyte progenitor cell proliferation. Our previous study demonstrates that netrin-1 overexpression improves neurobehavioral outcomes after ischemia by promoting focal angiogenesis. In this study, we investigate whether netrin-1 facilitates white matter recovery during focal ischemia and further to explore which specific receptor involves in the white matter reconstruction. Methods: sixty adult male ICR mice underwent adeno-associated virus (AAV) mediated AAV-Netrin-1 or AAV-GFPgene transfer. These mice received one hour transient middle artery occlusion (MCAO) and 7, 14, 28 days reperfusion at one week after the gene transfer. Western blot and immunohischemistry were used to determine the location and quantification of exogenous NT-1 expression. Neuronalbehavior test were performed to eveluate the neuralbehavioral outcomes. Oligodendrocyte progenietor cell proliferation, maturation and myelination were examined by immunohischemistry. Results: NT-1 was highly expressed in the mouse brain after two weeks of AAV-NT-1 gene transfer, which mainly expressed in neurons and astrocytes. Neurobehavioral outcomes were greatly improved at 7, 14 and 28 days after reperfusion in AAV-NT-1 treated mice compared to the GFP control mice ( p <0.05), The number of proliferated oligodendrocyte progenietor cells, mature oligodendrocytes and MBP positive neurofilaments in the corpus callosum and the striatum in the ipsilateral hemisphere at 7, 14 and 28 days after reperfusion were increased in the NT-1 treated group compared to GFP control mice ( p <0.01). NT-1 receptor DCC and Unc5H2 are involved in the proliferation of oligodendrocyte progenitor cells,But only Unc5h2 was involved in the re-myelination process. Conclusion: NT-1 overexpression improves neurobehavioral outcomes and promotes oligodendrocyte progenietor cell proliferation and maturation. Oue results suggest that netrin-1 not only promotes angiogenesis but also enchances remyelination.