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 neuritic plaques of Alzheimerʹs disease, activates astrocytes and enhances production and processing of β-amyloid precursor prptein (β-APP). Activated astrocytes, overexpressing S100β, are a prominent feature of these neuritic plaques, and the neurite growth-promoting properties of S100β have been implicated in the formation of dystrophic neurites overexpressing β-APP in neuritic plaques. These facts collectively suggest that elevated levels of the inflammatory cytokine IL-1 drive S100β and β-APP overexpression and dystrophic neurite formation in Alzheimerʹs disease. To more directly assess this driver potential for IL-1, we analyzed IL-1 induction of S100β expression in vivo and in vitro, and of β-APP expression in vivo. Synthetic IL-1β was injected into the right cerebral hemispheres of 13 rats. Nine additional rats were injected with phosphate-buffered saline, and seven rats served as uninjected controls. The number of astrocytes expressing detectable levels of S100β in tissue sections from IL-1-injected brains was 1.5 fold that of either control group (p < 0.01), while tissue S100β levels were approximately threefold that of controls (p < 0.05). The tissue levels of two β-APP isoforms (approximately 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 either IL-1β or IL-1α, showed significant increases in both S100β and S100 β mRNA levels. These results provide evidence that IL-1 upregulates both S100β and β-APP expression, in vivo and in vitro, and support the idea that overexpression of IL-1 in Alzheimerʹs disease drives astrocytic overexpression of S100β, favoring the growth of dystrophic neurites necessary for evolution of diffuse amyloid deposits into neuritic β-amyloid plaques.