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 Alzheimer's disease, activates astrocytes and enhances production and processing of beta-amyloid precursor protein (beta-APP). Activated astrocytes, overexpressing S100 beta, are a prominent feature of these neuritic plaques, and the neurite growth-promoting properties of S100 beta have been implicated in the formation of dystrophic neurites overexpressing beta-APP in neuritic plaques. These facts collectively suggest that elevated levels of the inflammatory cytokine IL-1 drive S100 beta and beta-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 S100 beta expression 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, and 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), while tissue S100 beta levels were approximately threefold that of controls (p < 0.05). The tissue levels of two beta-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-1 beta or IL-1 alpha, showed significant increases in both S100 beta and S100 beta mRNA levels. These results provide evidence that IL-1 upregulates both S100 beta and beta-APP expression, in vivo and vitro, and support the idea that overexpression of IL-1 in Alzheimer's disease drives astrocytic overexpression of S100 beta, favoring the growth of dystrophic neurites necessary for evolution of diffuse amyloid deposits into neuritic beta-amyloid plaques.
Sheng
J G
JG
Arkansas Children's Hospital Research Center, Department of Veterans' Affairs Medical Center, Little Rock, AR, USA.
Ito
K
K
Skinner
R D
RD
Mrak
R E
RE
Rovnaghi
C R
CR
Van Eldik
L J
LJ
Griffin
W S
WS
D000544:Alzheimer Disease / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D001932:Brain Neoplasms / Q000378:metabolism; D005910:Glioma / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007375:Interleukin-1 / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D009418:S100 Proteins / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; D007375:Interleukin-1; D009418:S100 Proteins