Abstract
The interaction of endogenous and exogenous stimulators of innate immunity was examined in primary cultures of mouse microglial cells and macrophages after application of defined Toll-like receptor (TLR) agonists [lipopolysaccharide (LPS) (TLR4), the synthetic lipopeptide Pam3Cys-Ser-Lys4 (Pam3Cys) (TLR2) and single-stranded unmethylated CpG-DNA (CpG) (TLR9)] alone and in combination with amyloid beta peptide (Abeta) 1-40. Abeta1-40 stimulated microglial cells and macrophages primed by interferon-gamma in a dose-dependent manner. Co-administration of Abeta1-40 with LPS or Pam3Cys led to an additive release of nitric oxide (NO) and tumour necrosis factor alpha (TNF-alpha). This may be one reason for the clinical deterioration frequently observed in patients with Alzheimer's disease during infections. In contrast, co-application of Abeta1-40 with CpG led to a substantial decrease of NO and TNF-alpha release compared with stimulation with CpG alone. Abeta1-40 and CpG did not co-localize within the same subcellular compartment, making a direct physicochemical interaction as the cause of the observed antagonism very unlikely. This suggests that not all TLR agonists enhance the stimulatory effect of A beta on innate immunity.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Peptides / pharmacology*
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Analysis of Variance
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Animals
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Animals, Newborn
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Blotting, Western / methods
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Brain / cytology
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Cell Survival / drug effects
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Cells, Cultured
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Cytokines / metabolism
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DNA, Bacterial / pharmacology
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DNA-Binding Proteins / antagonists & inhibitors*
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Dose-Response Relationship, Drug
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Drug Interactions
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Enzyme-Linked Immunosorbent Assay / methods
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Immunohistochemistry / methods
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Inflammation / chemically induced
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Inflammation / physiopathology*
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Lectins / metabolism
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Lipopolysaccharides / pharmacology*
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Lipoproteins / pharmacology*
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Macrophages / drug effects
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Mice
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Mice, Inbred C57BL
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Microglia / drug effects*
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Microglia / physiology
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Microscopy, Confocal / methods
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Nitrites / metabolism
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Peptide Fragments / metabolism
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Peptide Fragments / pharmacology*
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Receptors, Cell Surface / antagonists & inhibitors*
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Receptors, Immunologic / agonists*
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Toll-Like Receptor 9
Substances
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Amyloid beta-Peptides
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CpG-DNA, E coli
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Cytokines
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DNA, Bacterial
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DNA-Binding Proteins
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Lectins
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Lipopolysaccharides
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Lipoproteins
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Nitrites
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Peptide Fragments
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Receptors, Cell Surface
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Receptors, Immunologic
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Tlr2 protein, mouse
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Tlr4 protein, mouse
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Tlr9 protein, mouse
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Toll-Like Receptor 9
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amyloid beta-protein (1-40)
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N-palmitoyl-S-(2,3-bis(palmitoyloxy)propyl)cysteinyl-seryl-lysyl-lysyl-lysyl-lysine