Several hypotheses have been created to account for the neurodegeneration and subsequent cognitive deficits observed in Alzheimer disease (AD). 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. Additional studies are underway examining the ability of various beta amyloid peptides, gp120 proteins, and chemokines to directly induce gene expression in human and rodent astrocytes and neuronal cells. We believe that active transcriptional signals through cell membrane associated receptors play a significant role in the genesis of neuroinflammation and neurodegeneration in AD and AIDS. Using defined microarray gene chips, we are examining the expression of known and unknown genes induced post cell surface receptor ligation or viral infection. We believe that the identification and examination of induced or suppressed genes will not only provide insight into the pathogenesis of AD and AIDS but may also elucidate the molecular mechanisms of inflammation and the various signaling defects observed in aged cell populations.
