Several hypotheses have been created to account for the neurodegeneration and subsequent cognitive deficits observed in Alzheimer 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 neuronal tissue and cell signaling. Initial studies have demonstrated that the intracerebral infusion of endotoxin or TNFa 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 have observed differences in the induction of various inflammatory cytokines (i.e., IL-6, MCP-1, and MIP-2) within young and old rodent brain homogenates and plasma post treatment. Moreover, a number of direct effects have been observed in young and old animals post cytokine or endotoxin administration including effects on brain inflammation, the permeability of the blood-brain barrier, effects on leukocyte trafficking, alterations in cell surface markers, neurodegeneration, and alterations in 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. This is supported by our recent studies demonstrating that certain chemokines directly mediate neuronal cell apoptosis both in vitro and in vivo. Additional studies will be performed to determine whether administration of signaling inhibitors, anti-oxidants, and/or chemokine/cytokine antagonists 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, HIV-1 dementia, and age-related disease states such as Alzheimer Disease. - Neuroinflammation, Alzheimer's Disease, Cytokines, Chemokines
