Cytokine and Anti-Inflammatory Drug Effects on Brain Trauma and Alzheimer’s Disease Pathology in Transgenic Mice

Abstract

There is a continuous interaction between neurons, glia and inflammatory cells in the normal brain that is exacerbated following trauma or neurodegenerative disease. Cytokines mediate many of these interactions in injury and disease, and they may also play key roles in the developing and normal adult brain. Experiments using mice with targeted mutations in the gene for one of these cytokines, leukemia inhibitory factor (LIF), demonstrate that this protein is required for appropriate cell and behavioral responses to trauma in the nervous system. We find that LIF is induced by physical injury or chemically-induced inflammation, and in the absence of this cytokine, neuronal, astrocytic, microglial, neutrophil, macrophage and pain responses to these insults are strikingly altered. The specific effects of LIF deficiency depend critically on the site and type of injury, however. The inflammatory response can also be important in the establishment and/or progression of neurodegenerative disease. To study this we are using a transgenic mouse model of Alzheimer’s disease (AD). Preliminary results indicate that stressing the animals can strongly up-regulate the microglial reaction around senile plaques.