Amyloid-beta peptide (Abeta1-42), the cleavage product of the evolutionary highly conserved amyloid precursor protein, presumably plays a pathogenic role in Alzheimer's disease. Abeta1-42 can induce the secretion of the pro-inflammatory cytokine intereukin-1beta (IL-1beta) in immune cells within and out of the nervous system. Known interaction partners of Abeta1-42 are alpha7 nicotinic acetylcholine receptors (nAChRs). The physiological functions of Abeta1-42 are, however, not fully understood. Recently, we identified a cholinergic mechanism that controls monocytic release of IL-1beta by canonical and non-canonical agonists of nAChRs containing subunits alpha7, alpha9, and/or alpha10. Here, we tested the hypothesis that Abeta1-42 modulates this inhibitory cholinergic mechanism. Lipopolysaccharide-primed monocytic U937 cells and human mononuclear leukocytes were stimulated with the P2X7 receptor agonist 2'(3')-O-(4-benzoylbenzoyl)adenosine-5'-triphosphate triethylammonium salt (BzATP) in the presence or absence of nAChR agonists and Abeta1-42. IL-1beta concentrations were measured in the supernatant. Abeta1-42 dose-dependently (IC50 = 2.54 microM) reversed the inhibitory effect of canonical and non-canonical nicotinic agonists on BzATP-mediated IL-1beta-release by monocytic cells, whereas reverse Abeta42-1 was ineffective. In conclusion, we discovered a novel pro-inflammatory Abeta1-42 function that enables monocytic IL-1beta release in the presence of nAChR agonists. These findings provide evidence for a novel physiological function of Abeta1-42 in the context of sterile systemic inflammation.
- Richter, K.
- Ogiemwonyi-Schaefer, R.
- Wilker, S.
- Chaveiro, A. I.
- Agne, A.
- Hecker, M.
- Reichert, M.
- Amati, A. L.
- Schluter, K. D.
- Manzini, I.
- Schmalzing, G.
- McIntosh, J. M.
- Padberg, W.
- Grau, V.
- Hecker, A.
Keywords
- P2X7 receptor
- adenosine triphosphate
- amyloid beta peptide
- interleukin-1beta
- monocytes
- nicotinic acetylcholine receptors
- purinergic signaling
- systemic inflammation