Expression of the Alzheimer amyloid-promoting factor antichymotrypsin is induced in human astrocytes by IL-1.
The amyloid deposits of Alzheimer's disease contain, in addition to the beta protein (A beta), lesser amounts of other proteins including the protease inhibitor alpha 1-antichymotrypsin (ACT). We have recently shown that ACT acts as a pathological chaperone, binding to the beta protein and strongly promoting its polymerization into amyloid filaments in vitro. The data of this paper show that ACT synthesis is induced in cultured human astrocytes by IL-1, a lymphokine whose expression is strongly up-regulated in microglial cells in affected areas of Alzheimer's disease brain. Furthermore, unfractionated glial cultures containing both astrocytes and microglia from human cortex (which develops amyloid in Alzheimer's disease) spontaneously express IL-1 and ACT as they reach confluence. In contrast, confluent mixed glial cultures similarly prepared from human cerebellum or brain stem, or from rat brain-tissues not prone to amyloid formation-do not express ACT unless supplemented with exogenous IL-1. The same regional difference in IL-1 expression by microglia is seen in vivo in Alzheimer's disease. These results indicate that the IL-1-induced expression of ACT may help direct the region-specific production of mature amyloid filaments in the Alzheimer brain.
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115.
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D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D001933:Brain Stem / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D006801:Humans; D017403:In Situ Hybridization; D007375:Interleukin-1 / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D009928:Organ Specificity; D051381:Rats; D000514:alpha 1-Antichymotrypsin / Q000096:biosynthesis*
D016229:Amyloid beta-Peptides; D005904:Glial Fibrillary Acidic Protein; D007375:Interleukin-1; D000514:alpha 1-Antichymotrypsin; D003907:Dexamethasone