Effect of cytokines, dexamethasone and the A/T-signal peptide polymorphism on the expression of alpha(1)-antichymotrypsin in astrocytes: significance for Alzheimer's disease.
Proinflammatory cytokines and acute phase proteins, such as alpha(1)-antichymotrypsin, are over expressed in microglia and astrocytes in brain regions with abundant mature amyloid plaques, suggesting a glial cell-led brain acute phase response in the Alzheimer neuropathology. In this paper, we show that alpha(1)-antichymotrypsin gene expression in human astrocytes is elevated by interleukin-1 and interleukin-6, and further enhanced by glucocorticoid, while the homologous contrapsin gene in rat astrocytes is unaffected by these cytokines. These distinct gene regulation mechanisms might help to explain the differential susceptibility of humans and rodents to amyloid formation of the Alzheimer's type. In addition, we demonstrate that the alpha(1)-antichymotrypsin A-allele that encodes a different signal peptide and is a suggested risk factor for Alzheimer's disease gives rise to a reduced level of immature alpha(1)-antichymotrypsin in transfected cells. The physiological result would be an enhanced ability of the A-encoded alpha(1)-antichymotrypsin protein to become secreted and promote extracellular amyloid formation. We discuss our findings in terms of a model in which cytokine-induced alpha(1)-antichymotrypsin synthesis in astrocytes constitutes a specific inflammatory pathway that accelerates the development of Alzheimer's disease and could at least partly underlie the regional specificity and species restriction of the neuropathology.
Nilsson
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Suncoast Gerontology Center, Department of Biochemistry and Molecular Biology and Moffitt Cancer Center, College of Medicine, MDC07, University of South Florida, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA. lnilsson@hsc.usf.edu
Das
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Potter
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D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D011110:Polymorphism, Genetic / Q000502:physiology*; D014176:Protein Biosynthesis; D021382:Protein Sorting Signals / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015843:Serpins; D014361:Trypsin Inhibitors / Q000235:genetics; D000514:alpha 1-Antichymotrypsin / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D005938:Glucocorticoids; D021382:Protein Sorting Signals; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015843:Serpins; D014361:Trypsin Inhibitors; D000514:alpha 1-Antichymotrypsin; D003994:Bucladesine; D003907:Dexamethasone; C033691:contrapsin