Proinflammatory effects of M-CSF and A beta in hippocampal organotypic cultures.

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.