Neurodegenerative disorders including Alzheimer＇s disease are characterized by chronic in- flammation in the central nervous system. The two main glial types involved in inflammatory reactions are microglia and astro...Neurodegenerative disorders including Alzheimer＇s disease are characterized by chronic in- flammation in the central nervous system. The two main glial types involved in inflammatory reactions are microglia and astrocytes. While these cells normally protect neurons by providing nutrients and growth factors, disease specific stimuli can induce glial secretion of neurotoxins. It has been hypothesized that reducing glia-mediated inflammation could diminish neuronal loss. This hypothesis is supported by observations that chronic use of non-steroidal anti-inflamma- tory drugs （NSAIDs） is linked with lower incidences of neurodegenerative disease. It is possible that the NSAIDs are not potent enough to appreciably reduce chronic neuroinflammation after disease processes are fully established. Gold thiol compounds, including auranofin, comprise an- other class of medications effective at reducing peripheral inflammation. We have demonstrated that auranofin inhibits human microglia- and astrocyte-mediated neurotoxicity. Other drugs which are currently used to treat peripheral inflammatory conditions could be helpful in neu- rodegenerative disease. Three different classes of anti-inflammatory compounds, which have a potential to inhibit neuroinflammation are highlighted below.展开更多
Aim:Submicron fragments termed microparticles(MPs),derived from all major central nervous system cell types including neurons and glia(microglia,astrocytes,oligodendrocytes),have emerged as novel intercellular signali...Aim:Submicron fragments termed microparticles(MPs),derived from all major central nervous system cell types including neurons and glia(microglia,astrocytes,oligodendrocytes),have emerged as novel intercellular signaling agents.This study tested the hypothesis that MPs derived from activated microglia,which represent the mononuclear phagocyte system in the brain,could induce pro-inflammatory and cytotoxic responses of microglia in an autocrine or paracrine manner.Methods:Human THP-1 monocytic cells were used to model human microglia.MPs derived from these cells were reapplied to THP-1 cells and their secretion of neurotoxins and cytokines was measured.Results:When exposed to lipopolysaccharide(LPS)or mitochondrial transcription factor A in combination with interferon(IFN)-γ,THP-1 cells released MPs.When reapplied to THP-1 cells,MPs induced the release of secretions that were toxic to human SH-SY5Y neuroblastoma cells,as well as monocyte chemoattractant protein-1.The cytotoxicity of THP-1 cells induced by MPs derived from IFN-γplus LPS-treated THP-1 donor cells was enhanced in the presence of IFN-γ.The MPs released by THP-1 cells were not directly toxic towards SH-SY5Y cells.Conclusion:Our data support the hypothesis that activated microglia-derived MPs could act as signaling agents that are recognized by microglia to cause pro-inflammatory and cytotoxic responses.展开更多
基金supported by a grant from the Jack BrownFamily Alzheimer’s Disease Research Foundation
文摘Neurodegenerative disorders including Alzheimer＇s disease are characterized by chronic in- flammation in the central nervous system. The two main glial types involved in inflammatory reactions are microglia and astrocytes. While these cells normally protect neurons by providing nutrients and growth factors, disease specific stimuli can induce glial secretion of neurotoxins. It has been hypothesized that reducing glia-mediated inflammation could diminish neuronal loss. This hypothesis is supported by observations that chronic use of non-steroidal anti-inflamma- tory drugs （NSAIDs） is linked with lower incidences of neurodegenerative disease. It is possible that the NSAIDs are not potent enough to appreciably reduce chronic neuroinflammation after disease processes are fully established. Gold thiol compounds, including auranofin, comprise an- other class of medications effective at reducing peripheral inflammation. We have demonstrated that auranofin inhibits human microglia- and astrocyte-mediated neurotoxicity. Other drugs which are currently used to treat peripheral inflammatory conditions could be helpful in neu- rodegenerative disease. Three different classes of anti-inflammatory compounds, which have a potential to inhibit neuroinflammation are highlighted below.
基金supported by grants from the Jack Brown and Family Alzheimer’s Disease Research Foundation,the Natural Sciences and Engineering Research Council of Canada,and the University of British Columbia Okanagan Campus.
文摘Aim:Submicron fragments termed microparticles(MPs),derived from all major central nervous system cell types including neurons and glia(microglia,astrocytes,oligodendrocytes),have emerged as novel intercellular signaling agents.This study tested the hypothesis that MPs derived from activated microglia,which represent the mononuclear phagocyte system in the brain,could induce pro-inflammatory and cytotoxic responses of microglia in an autocrine or paracrine manner.Methods:Human THP-1 monocytic cells were used to model human microglia.MPs derived from these cells were reapplied to THP-1 cells and their secretion of neurotoxins and cytokines was measured.Results:When exposed to lipopolysaccharide(LPS)or mitochondrial transcription factor A in combination with interferon(IFN)-γ,THP-1 cells released MPs.When reapplied to THP-1 cells,MPs induced the release of secretions that were toxic to human SH-SY5Y neuroblastoma cells,as well as monocyte chemoattractant protein-1.The cytotoxicity of THP-1 cells induced by MPs derived from IFN-γplus LPS-treated THP-1 donor cells was enhanced in the presence of IFN-γ.The MPs released by THP-1 cells were not directly toxic towards SH-SY5Y cells.Conclusion:Our data support the hypothesis that activated microglia-derived MPs could act as signaling agents that are recognized by microglia to cause pro-inflammatory and cytotoxic responses.
