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Interleukin-1 (IL-1), an inflammatory cytokine overexpressed in the neuritic plaques of Alzheimer's disease, activates astrocytes and enhances production and processing of (β-amyloid precursor protein (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 Alzheimer's 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 S100β 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 Alzheimer's disease drives astrocytic overexpression of S100β, favoring the growth of dystrophic neurites necessary for evolution of diffuse amyloid deposits into neuritic β-amyloid plaques. KeywordsInterleukin-1; S100β; β-Amyloid precursor protein; Alzheimer's disease; Down's syndrome; Rats; C6 glioma cellsThe global intellectual decline of Alzheimer's disease is accompanied by a profusion of microscopic brain lesions that contain extracellular fibrillar material in a β-pleated sheet Copyright © 1996 conformation (β-amyloid), abnormal neuronal processes ("dystrophic" neurites) overexpressing β-amyloid precursor protein (β-APP), and activated glia (astrocytes and microglia). The possible interactions of these plaque-associated astrocytes and microglia, their armamentarium of overexpressed cytokines and other molecules, and the known actions of these cytokines and molecules bear sufficient parallels to chronic, focal inflammatory processes found outside the nervous system to suggest that the basic driving pathophysiological mechanism in Alzheimer's disease is fundamentally an inflammatory one (21).The plaques of Alzheimer's disease are thought to originate as diffuse deposits of nonpleated amyloid protein ('diffuse nonneuritic' plaques) that progress to more classic 'diffuse neuritic' plaques (commonly referred to as immature plaques) composed of β-pleated amyl...

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