IN-VIVO AND IN-VITRO EVIDENCE SUPPORTING A ROLE FOR THE INFLAMMATORY CYTOKINE INTERLEUKIN-1 AS A DRIVING-FORCE IN ALZHEIMER PATHOGENESIS

Interleukin-1 (IL-1), an inflammatory cytokine overexpressed in the ne uritic plaques of Alzheimer's disease, activates astrocytes and enhanc es production and processing of beta-amyloid precursor protein (beta-A PP). Activated astrocytes, overexpressing S100 beta, are a prominent f eature of these neuritic plaques, and the neurite growth-promoting pro perties of S100 beta have been implicated in the formation of dystroph ic neurites overexpressing beta-APP in neuritic plaques. These facts c ollectively suggest that elevated levels of the inflammatory cytokine IL-1 drive S100 beta and beta-APP overexpression and dystrophic neurit e formation in Alzheimer's disease. To more directly assess this drive r potential for IL-1, we analyzed IL-1 induction of S100 beta expressi on in vivo and in vitro, and of beta-APP expression in vivo. Synthetic IL-1 beta was injected into the right cerebral hemispheres of 13 rats . Nine additional rats were injected with phosphate-buffered saline, a nd seven rats served as uninjected controls. The number of astrocytes expressing detectable levels of S100 beta in tissue sections from IL-1 -injected brains was 1.5 fold that of either control group (p<0.01), w hile tissue S100 beta levels were approximately threefold that of cont rols (p<0.05). The tissue levels of two beta-APP isoforms (approximate ly 130 and 135 kDa) were also significantly elevated in IL-1-injected brains (p<0.05). C6 glioma cells, treated in vitro for 24 h with eithe r IL-1 beta or IL-1 alpha, showed significant increases in both S100 b eta and S100 beta mRNA levels. These results provide evidence that IL- 1 upregulates both S100 beta and beta-APP expression, in vivo and in v itro, and support the idea that overexpression of IL-1 in Alzheimer's disease drives astrocytic overexpression of S100 beta, favoring the gr owth of dystrophic neurites necessary for evolution of diffuse amyloid deposits into neuritic beta-amyloid plaques.