Thrombospondin1 Enhanced Neuronal Wnt7a and CNTF Expressions by TNFα Signaling Pathway

Abstract

Abstract Background: Thrombospondin (TSP) is an astrocyte-secreted protein, well-known for its function as a modulator of synaptogenesis and neurogenesis. The mechanism underlying the effects of TSP1 on synaptic activity and formation involved in MHE pathogenesis remains unclear. Methods: The present study explored the effect of TSP1 on neurodegeneration, inflammatory response and the activation of Wnt7a/CNTF signaling in the primary rat neurons and an MHE rat model. Results: When we treated neurons with TSP1, p38MAPK phosphorylation and TNFα expression was increased significantly. Also, the exposure of TSP1 increased the expression and release of Wnt7a and CNTF, upregulated spinophilin, enhanced the interaction of Wnt7a/CNTF with spinophilin, and triggered synaptic activity through p38/TNFα signaling in PC12 cells and primary neurons. The hippocampal injection of TSP1 siRNA in mice decreased the interaction of Wnt7a/CNTF with spinophilin, while injection of Wnt7a and CNTF improved learning and memory dysfunctions. MHE brains showed decreased TSP1 expression. The overexpression of TSP1 in the hippocampus of MHE rats ameliorated the disrupted synaptogenesis, learning, and memory. Conclusions: Taken together, these results indicated that TSP1 is a potential synaptic factor related to the inflammatory response and the activation of Wnt7a/CNTF signaling in MHE pathogenesis.</jats:p