Amyloid beta peptide 1–40 enhances the action of Toll‐like receptor‐2 and ‐4 agonists but antagonizes Toll‐like receptor‐9‐induced inflammation in primary mouse microglial cell cultures

• Published in: Journal of neurochemistry 2005-07, Vol.94 (2), p.289-298
• Main Authors: Lotz, Miriam, Ebert, Sandra, Esselmann, Hermann, Iliev, Asparouh I., Prinz, Marco, Wiazewicz, Nicole, Wiltfang, Jens, Gerber, Joachim, Nau, Roland
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; amyloid beta 1–40 peptide; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - pharmacology; Analysis of Variance; Animals; Animals, Newborn; Biological and medical sciences; Blotting, Western - methods; Brain - cytology; Cell receptors; Cell structures and functions; Cell Survival - drug effects; Cells; Cells, Cultured; Cytokines - metabolism; cytosin‐guanosin oligodesoxynucleotide; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA, Bacterial - pharmacology; DNA-Binding Proteins - antagonists & inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Enzyme-Linked Immunosorbent Assay - methods; Fundamental and applied biological sciences. Psychology; Immunohistochemistry - methods; Inflammation - chemically induced; Inflammation - physiopathology; Lectins - metabolism; lipopolysaccharide; Lipopolysaccharides - pharmacology; Lipoproteins - pharmacology; Macrophages - drug effects; Medical sciences; Mice; Mice, Inbred C57BL; microglia; Microglia - drug effects; Microglia - physiology; Microscopy, Confocal - methods; Molecular and cellular biology; Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine); Neurology; Neurotransmitters; nitric oxide; Nitrites - metabolism; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Peptides; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Immunologic - agonists; Rodents; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptor 9; tripalmytoyl‐cysteinyl‐seryl‐(lysyl)3‐lysine
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2005.03188.x

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. Abeta 1–40 stimulated microglial cells and macrophages primed by interferon‐γ 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‐α). 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‐ α release compared with stimulation with CpG alone. Abeta 1–40 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 Abeta on innate immunity.