?-Amyloid protein enhances macrophage production of oxygen free radicals and glutamate

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Abstract
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 β-amyloid peptide Aβ (1–40); but not by treatment with the reverse Aβ (40–1) or the Aβ (25–35) subfragment. Superoxide anion production by the cells was stimulated by OZ, PMA, Aβ (1–40), and Aβ (25–35). Moreover, Aβ 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 Aβ, 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. J. Neurosci. Res. 49:229–235, 1997.