Several hypotheses have been created to account for the neurodegeneration and subsequent cognitive deficits observed in Alzheimer's disease. One hypothesis, in particular, has focused on the effects of inflammation as a mediator of neurodegeneration. To address this possibility, we have initiated studies examining the direct and indirect effects that endotoxin and inflammatory cytokines may have on neural tissue and neuronal cell signaling. Initial studies have demonstrated that the intracerebral infusion of endotoxin produces a significant age-related increase in brain tumor necrosis factor- alpha (TNFa) levels, but does not effect the production of a number of other inflammatory cytokines such as interleukin-1 or interleukin-12. We are currently examining young and old rodent brain homogenates and plasma post endotoxin treatment for the presence of various inflammatory cytokines (e.g., interleukin-6, interleukin-4, interleukin-10) and chemokines (e.g., interleukin- 8, MCP-1). Moreover,animals are also being examined for the effects of direct cytokine administration on inducing brain inflammation, permeabilizing of the blood-brain barrier, and effects on leukocyte trafficking, CNS surface markers, neurodegeneration, and cognitive behavior. We believe that cytokine and chemokine infusion (icv and iv) in rodent brains will have significant biological and physiological effects on neural tissue and will ultimately reveal a relationship between neuroinflammation, age, and cognitive behavior. These studies have been initiated using intracerebral TNF-a infusion and we hope to soon follow these efforts with chemokine and interferon infusions. In addition, additional studies will also be performed to determine whether administration of signaling inhibitors and antagonists and/or through in vivo leukocyte depletion can ameliorate the biological and physiological effects of administered cytokines. It is our hope that these efforts will assist in our understanding of the contribution of cytokines and chemokines in the neuroinflammatory and neurodegenerative effects observed in various neurotrauma models and age-related disease states.
