In Vivo and In Vitro Evidence Supporting a Role for the Inflammatory Cytokine Interleukin-1 as a Driving Force in Alzheimer Pathogenesis

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• 作者：Sheng ; Jin G. ; Ito ; Kazuhiro ; Skinner ; Robert D. ; Mrak ; Robert E. ; Rovnaghi ; Cynthia R. ; Van Eldik ; Linda J. ; et. al.
• 关键词：Interleukin-1 ; S100β ; β ; -Amyloid precursor protein ; Alzheimer's disease ; Down's syndrome ; Rats ; C6 glioma cells
• 刊名：Neurobiology of Aging
• 出版年：1996
• 出版时间：September 10, 1996
• 年：1996
• 卷：17
• 期：5
• 页码：761-766
• 全文大小：866 K

文摘

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.