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  • Title: IL-1β suppresses cLTP-induced surface expression of GluA1 and actin polymerization via ceramide-mediated Src activation.
    Author: Tong L, Prieto GA, Cotman CW.
    Journal: J Neuroinflammation; 2018 Apr 30; 15(1):127. PubMed ID: 29712570.
    Abstract:
    BACKGROUND: Brain inflammation including increases in inflammatory cytokines such as IL-1β is widely believed to contribute to the pathophysiology of Alzheimer's disease. Although IL-1β-induced impairments in long-term potentiation (LTP) in acute hippocampal slices and memory functions in vivo have been well documented, the neuron-specific molecular mechanisms of IL-1β-mediated impairments of LTP and memory remain unclear. METHODS: This study uses an in vitro approach in primary hippocampal neurons to evaluate the effect of IL-1β on chemical LTP (cLTP)-induced structural plasticity and signaling. RESULTS: We found that IL-1β reduces both the surface expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 and the spine growth following cLTP. These effects of IL-1β were mediated by impairing actin polymerization during cLTP, as IL-1β decreased the cLTP-induced formation of F-actin, and the effect of IL-1β on cLTP-induced surface expression of GluA1 can be mimicked by latrunculin, a toxin that disrupts dynamics of actin filaments, and can be prevented by jasplakinolide, a cell-permeable peptide that stabilizes F-actin. Moreover, live-cell imaging demonstrated that IL-1β decreased the stability of the actin cytoskeleton in spines, which is required for LTP consolidation. We further examined the role of sphingolipid signaling in the IL-1β-mediated impairment of spine plasticity and found that both the neutral sphingomyelinase inhibitor GW4869 and the inhibitor of Src kinase PP2 attenuated the IL-1β-mediated suppression of cLTP-induced surface expression of GluA1 and actin polymerization. CONCLUSIONS: These findings support a mechanism by which IL-1β, via the sphingomyelinase/ceramide/Src pathway, impairs structural spine remodeling essential for LTP consolidation and memory.
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