Alzheimer's beta-amyloid peptides induce inflammatory cascade in human vascular cells: the roles of cytokines and CD40.
Accumulating evidence suggests that beta-amyloid (Abeta)-induced inflammatory reactions may partially drive the pathogenesis of Alzheimer's disease (AD). Recent data also implicate similar inflammatory processes in cerebral amyloid angiopathy (CAA). To evaluate the roles of Abeta in the inflammatory processes in vascular tissues, we have tested the ability of Abeta to trigger inflammatory responses in cultured human vascular cells. We found that stimulation with Abeta dose-dependently increased the expression of CD40, and secretion of interferon-gamma (IFN-gamma) and interleukin-1beta (IL-1beta) in endothelial cells. Abeta also induced expression of IFN-gamma receptor (IFN-gammaR) both in endothelial and smooth muscle cells. Characterization of the Abeta-induced inflammatory responses in the vascular cells showed that the ligation of CD40 further increased cytokine production and/or the expression of IFN-gammaR. Moreover, IL-1beta and IFN-gamma synergistically increased the Abeta-induced expression of CD40 and IFN-gammaR. We have recently found that Abeta induces expression of adhesion molecules, and that cytokine production and interaction of CD40-CD40 ligand (CD40L) further increase the Abeta-induced expression of adhesion molecules in these same cells. These results suggest that Abeta can function as an inflammatory stimulator to activate vascular cells and induces an auto-amplified inflammatory molecular cascade, through interactions among adhesion molecules, CD40-CD40L and cytokines. Additionally, Abeta1-42, the more pathologic form of Abeta, induces much stronger effects in endothelial cells than in smooth muscle cells, while the reverse is true for Abeta1-40. Collectively, these findings support the hypothesis that the Abeta-induced inflammatory responses in vascular cells may play a significant role in the pathogenesis of CAA and AD.
Roskamp Institute, 3515 E. Fletcher Avenue, University of South Florida, Tampa, FL 33613, USA. zsuo@com1.med.usf.edu
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Z
Suo
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J
Tan
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Placzek
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Crawford
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C
Fang
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M
Mullan
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D019013:CD40 Antigens / Q000276:immunology*; D002460:Cell Line; D016207:Cytokines / Q000502:physiology*; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D017471:Receptors, Interferon / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation; D000096743:Interferon gamma Receptor
D016229:Amyloid beta-Peptides; D019013:CD40 Antigens; D016207:Cytokines; D019040:E-Selectin; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D007375:Interleukin-1; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor