Science and Research

Amyloid Beta Peptide (Abeta1-42) Reverses the Cholinergic Control of Monocytic IL-1beta Release

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
Publication details
DOI: 10.3390/jcm9092887
Journal: J Clin Med
Number: 9
Work Type: Original
Location: UGMLC
Disease Area: ROR
Partner / Member: JLU
Access-Number: 32906646
See publication on PubMed

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