Abstract
Neuroinflammation is a striking hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Previous studies have shown the contribution of glial cells such as astrocytes in TDP-43-linked ALS. However, the role of microglia in TDP-43-mediated motor neuron degeneration remains poorly understood. In this study, we show that depletion of TDP-43 in microglia, but not in astrocytes, strikingly upregulates cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production through the activation of MAPK/ERK signaling and initiates neurotoxicity. Moreover, we find that administration of celecoxib, a specific COX-2 inhibitor, greatly diminishes the neurotoxicity triggered by TDP-43-depleted microglia. Taken together, our results reveal a previously unrecognized non-cell-autonomous mechanism in TDP-43-mediated neurodegeneration, identifying COX-2-PGE2 as the molecular events of microglia- but not astrocyte-initiated neurotoxicity and identifying celecoxib as a novel potential therapy for TDP-43-linked ALS and possibly other types of ALS.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyotrophic Lateral Sclerosis / drug therapy*
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Amyotrophic Lateral Sclerosis / genetics
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Amyotrophic Lateral Sclerosis / pathology
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Animals
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Astrocytes / metabolism
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Astrocytes / pathology
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Celecoxib / administration & dosage
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Cell Death / drug effects
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Cell Death / genetics
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Cell Line
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Cyclooxygenase 2 / biosynthesis*
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Cyclooxygenase 2 / genetics
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Dinoprostone / biosynthesis*
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Dinoprostone / genetics
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Gene Expression Regulation / drug effects
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Humans
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / genetics
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Mice
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Microglia / drug effects
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Microglia / metabolism
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Microglia / pathology
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Mitogen-Activated Protein Kinase Kinases / drug effects
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Mitogen-Activated Protein Kinase Kinases / genetics
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Motor Neurons / drug effects
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Motor Neurons / metabolism*
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Motor Neurons / pathology
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Nerve Degeneration / drug therapy
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Nerve Degeneration / genetics
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Nerve Degeneration / pathology
Substances
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DNA-Binding Proteins
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TDP-43 protein, mouse
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Ptgs2 protein, mouse
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Cyclooxygenase 2
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Mitogen-Activated Protein Kinase Kinases
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Celecoxib
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Dinoprostone