Abstract
Colony-stimulating factor 1 (CSF1) and interleukin-34 (IL-34) are functional ligands of the CSF1 receptor (CSF1R) and thus are key regulators of the monocyte/macrophage lineage. We discovered that systemic administration of human recombinant CSF1 ameliorates memory deficits in a transgenic mouse model of Alzheimer's disease. CSF1 and IL-34 strongly reduced excitotoxin-induced neuronal cell loss and gliosis in wild-type mice when administered systemically before or up to 6 h after injury. These effects were accompanied by maintenance of cAMP responsive element-binding protein (CREB) signaling in neurons rather than in microglia. Using lineage-tracing experiments, we discovered that a small number of neurons in the hippocampus and cortex express CSF1R under physiological conditions and that kainic acid-induced excitotoxic injury results in a profound increase in neuronal receptor expression. Selective deletion of CSF1R in forebrain neurons in mice exacerbated excitotoxin-induced death and neurodegeneration. We conclude that CSF1 and IL-34 provide powerful neuroprotective and survival signals in brain injury and neurodegeneration involving CSF1R expression on neurons.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid beta-Protein Precursor / genetics
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Animals
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Base Sequence
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Cell Survival
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Cognition / drug effects
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Cyclic AMP Response Element-Binding Protein / immunology
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Cyclic AMP Response Element-Binding Protein / metabolism
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Disease Models, Animal
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Humans
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Interleukins / genetics
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Interleukins / pharmacology
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Kainic Acid / toxicity
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Macrophage Colony-Stimulating Factor / administration & dosage
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Macrophage Colony-Stimulating Factor / genetics
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Macrophage Colony-Stimulating Factor / metabolism
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Macrophage Colony-Stimulating Factor / pharmacology*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Molecular Sequence Data
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Neurodegenerative Diseases / drug therapy
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Neurodegenerative Diseases / metabolism
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Neurodegenerative Diseases / pathology
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Neurons / drug effects
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Neurons / metabolism*
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Neurons / pathology
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Neuroprotective Agents / pharmacology
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Phosphorylation
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Prosencephalon / metabolism
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Prosencephalon / pathology
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Receptor, Macrophage Colony-Stimulating Factor / genetics
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Receptor, Macrophage Colony-Stimulating Factor / metabolism*
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Recombinant Proteins / genetics
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Recombinant Proteins / pharmacology
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Signal Transduction
Substances
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APP protein, human
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Amyloid beta-Protein Precursor
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Creb1 protein, mouse
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Cyclic AMP Response Element-Binding Protein
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Interleukins
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Neuroprotective Agents
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Recombinant Proteins
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interleukin-34, mouse
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Macrophage Colony-Stimulating Factor
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Receptor, Macrophage Colony-Stimulating Factor
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Kainic Acid