beta-amyloid protein enhances macrophage production of oxygen free radicals and glutamate.
Cells of the monocyte phagocytic system can generate superoxide and glutamate anions, both of which are neurotoxic at high levels. We used rat peritoneal macrophages as a model system to test the effects of various stimulants on the production of these molecules. Glutamate production by such cells was enhanced, in a concentration-dependent manner, by treatment with serum-opsonized zymosan (OZ), lipopolysaccharide (LPS), phorbol myristate acetate (PMA), and beta-amyloid peptide Abeta (1-40); but not by treatment with the reverse Abeta (40-1) or the Abeta (25-35) subfragment. Superoxide anion production by the cells was stimulated by OZ, PMA, Abeta (1-40), and Abeta (25-35). Moreover, Abeta and its subfragment, when used as priming agents, also enhanced the stimulatory effect of PMA. However, they did not act as priming agents for OZ, suggesting a competition for receptors or intracellular signaling pathways linked to those receptors. Inflammatory mediators, including Abeta, could place glutamate-sensitive neurons at risk by enhancing glutamate and oxygen free radical production by monocyte-derived cells. Such mechanisms could contribute to the pathogenesis of neurodegenerative disorders, including Alzheimer's disease.
Klegeris
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Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, Canada. kinsmen@unixg.ubc.ca
McGeer
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PL
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D005609:Free Radicals; D018698:Glutamic Acid / Q000096:biosynthesis*; D008163:Luminescent Measurements; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016897:Respiratory Burst / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism
D016229:Amyloid beta-Peptides; D005609:Free Radicals; D017382:Reactive Oxygen Species; D013481:Superoxides; D018698:Glutamic Acid