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Proinflammatory effects of M-CSF and A beta in hippocampal organotypic cultures
Valerie A M Vincent1, Simon P Selwood, Greer M Murphy
1Department of Psychiatry and Behavioral Sciences, Neuroscience Research Laboratories, Stanford University School of Medicine, Stanford, CA 94305-5485, USA.
Abstract:
Macrophage colony stimulating factor (M-CSF) is a microglial activator expressed at increased levels in the brain in Alzheimer's disease. In monotypic microglial cultures, M-CSF strongly augments amyloid beta (Abeta) induced microglial production of proinflammatory cytokines and nitric oxide. However, this augmentation could be due to strong autocrine and paracrine effects in monotypic cultures. We used hippocampal organotypic cultures to test M-CSF/Abeta augmentation in a system modeling intact brain. Combined M-CSF/Abeta treatment increased interleukin-1 (IL-1) and macrophage inflammatory protein 1-alpha expression by microglia, whereas inducible nitric oxide synthase (iNOS) expression was localized primarily to astroglia. Induction of cytokines and iNOS was also observed after lipopolysaccharide treatment of organotypic hippocampal cultures, but iNOS expression was localized mainly to microglia rather than astrocytes. Treatment with M-CSF/Abeta did not result in neuronal death. These results demonstrate that combined M-CSF/Abeta treatment results in a strong inflammatory response in the organotypic environment without inducing neurotoxicity.
Insights
Macrophage colony stimulating factor (M-CSF) and amyloid beta (Abeta) trigger inflammation in brain organotypic cultures. This M-CSF/Abeta combination causes a significant inflammatory response without causing neuronal death.
Area of Science:
- Neuroscience
- Immunology
- Alzheimer's Disease Research
Background:
- Macrophage colony stimulating factor (M-CSF) is elevated in Alzheimer's disease (AD) brains and activates microglia.
- M-CSF amplifies amyloid beta (Abeta)-induced inflammatory responses in isolated microglial cultures.
- Autocrine and paracrine signaling in monotypic cultures may influence M-CSF/Abeta effects.
Purpose of the Study:
- To investigate the effects of M-CSF and Abeta in a more physiologically relevant hippocampal organotypic culture model.
- To determine if M-CSF/Abeta treatment induces neurotoxicity in an intact brain environment.
Main Methods:
- Hippocampal organotypic cultures were treated with M-CSF and Abeta.
- Expression of inflammatory markers (IL-1, MIP-1alpha, iNOS) was analyzed.
- Neuronal survival was assessed after treatment.
- Comparison with lipopolysaccharide (LPS) treatment was performed.
Main Results:
- Combined M-CSF/Abeta treatment increased microglial expression of IL-1 and MIP-1alpha.
- Inducible nitric oxide synthase (iNOS) was primarily expressed in astroglia following M-CSF/Abeta treatment.
- LPS treatment induced iNOS mainly in microglia.
- M-CSF/Abeta treatment did not lead to neuronal death.
Conclusions:
- M-CSF/Abeta elicits a robust inflammatory response in organotypic hippocampal cultures.
- The inflammatory response involves both microglia and astroglia.
- This inflammatory response does not result in neurotoxicity in this model system.