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beta-amyloid protein enhances macrophage production of oxygen free radicals and glutamate
1Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, Canada. kinsmen@unixg.ubc.ca
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 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.
Insights
Monocyte cells produce neurotoxic superoxide and glutamate. Beta-amyloid peptide (Abeta) and other stimulants increase glutamate and superoxide production, potentially contributing to neurodegenerative diseases like Alzheimer's.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Monocyte phagocytic system cells can produce neurotoxic superoxide and glutamate anions.
- High levels of these molecules are implicated in neuronal damage.
Purpose of the Study:
- To investigate the effects of various stimulants on superoxide and glutamate anion production by rat peritoneal macrophages.
- To explore the role of beta-amyloid peptide (Abeta) in modulating these cellular responses.
Main Methods:
- Rat peritoneal macrophages were used as a model system.
- Cells were treated with stimulants including serum-opsonized zymosan (OZ), lipopolysaccharide (LPS), phorbol myristate acetate (PMA), and Abeta peptides.
- Glutamate and superoxide anion production were measured.
Main Results:
- Glutamate production was enhanced by OZ, LPS, PMA, and Abeta (1-40) in a concentration-dependent manner.
- Superoxide anion production was stimulated by OZ, PMA, Abeta (1-40), and Abeta (25-35).
- Abeta peptides acted as priming agents for PMA but not OZ, suggesting pathway competition.
Conclusions:
- Inflammatory mediators, including Abeta, can increase glutamate and oxygen free radical production by monocyte-derived cells.
- These mechanisms may contribute to the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease.