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.
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.
Department of Neurology, Georg-August-University, Göttingen, Germany.
Miriam
M
Lotz
Sandra
S
Ebert
Hermann
H
Esselmann
Asparouh I
AI
Iliev
Marco
M
Prinz
Nicole
N
Wiazewicz
Jens
J
Wiltfang
Joachim
J
Gerber
Roland
R
Nau
D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000166:cytology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004269:DNA, Bacterial / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D037102:Lectins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008074:Lipoproteins / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000502:physiology; D018613:Microscopy, Confocal / Q000379:methods; D009573:Nitrites / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D011971:Receptors, Immunologic / Q000819:agonists*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9
D016229:Amyloid beta-Peptides; C472452:CpG-DNA, E coli; D016207:Cytokines; D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D037102:Lectins; D008070:Lipopolysaccharides; D008074:Lipoproteins; D009573:Nitrites; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; C078592:amyloid beta-protein (1-40); C061108:N-palmitoyl-S-(2,3-bis(palmitoyloxy)propyl)cysteinyl-seryl-lysyl-lysyl-lysyl-lysine