Meeting Abstract

Authors list: Richter, K; Ogiemwonyi-Schaefer, R; Wilker, S; Chaveiro, A; Agné, A; Hecker, M; Reichert, M; Amati, AL; Schlüter, KD; Manzini, I; Schmalzing, G; McIntosh, J; Padberg, W; Grau, V; Hecker, A

Publication year: 2021

Journal: The FASEB Journal

Volume number: 35

Issue number: SI

ISSN: 0892-6638

eISSN: 1530-6860

DOI Link: https://doi.org/10.1096/fasebj.2021.35.S1.01474

Conference: Experimental Biology 2021

Publisher: Wiley

Abstract: 

Amyloid-β peptide (Aβ_1-42) plays a pathogenic role in Alzheimer´s disease. Its physiological functions are, however, still debated. Aβ_1-42 can induce the secretion of the pro-inflammatory cytokine intereukin-1β (IL-1β) by immune cells. Known interaction partners of Aβ_1-42 are α7 nicotinic acetylcholine receptors (nAChRs). Recently, we identified a cholinergic mechanism that inhibits the ATP-associated release of IL-1β by human monocytes via nAChRs containing α7, α9 and/or α10 subunits. Moreover, we discovered novel nAChR agonists that efficiently inhibit monocytic IL-1β release via a metabotropic mechanism. The objective of this study was to test if Aβ_1-42 can modulate this cholinergic mechanism. Human monocytic U937 cells and freshly isolated human peripheral blood mononuclear cells (approved by the ethics committee of the medical faculty Giessen, Germany, and performed in accordance with the Helsinki Declaration) were primed with lipopolysaccharide and ATP-induced IL-1β release in the presence or absence nAChR agonists and Aβ_1-42 was measured by enzyme-linked immunosorbent assay. We found that Aβ_1-42 dose-dependently (IC₅₀= 2.5 µM) antagonized the inhibitory effect of canonical and novel non-canonical nicotinic agonists like phosphocholine (100 µM), C-reactive protein (5 µg/mL) and glycerophosphocholine (10 µM), indicating a novel pro-inflammatory Aβ_1-42 function that enables monocytic IL-1β release in the presence of nAChR agonists. In whole-cell patch-clamp and calcium imaging experiments on human P2X7 receptor overexpressing HEK293 cells, no direct effect of Aβ_1-42 on P2X7 receptor activity was observed. In blood plasma samples from major surgery patients, IL-1β was mostly detected together with increased Aβ_1-42 levels, which is in line with our hypothesis. Taken together, our results suggest that Aβ_1-42 can antagonize the cholinergic control of ATP-mediated monocytic IL-1β-release and, thus, provide evidence for a novel function of Aβ_1-42 that also might be considered in situations of systemic inflammation.

Harvard Citation style: Richter, K., Ogiemwonyi-Schaefer, R., Wilker, S., Chaveiro, A., Agné, A., Hecker, M., et al. (2021) Amyloid beta peptide (Aβ1–42) antagonizes nicotinic acetylcholine receptors of monocytes and enables ATP-mediated release of interleukin-1β, The FASEB Journal, 35(SI). https://doi.org/10.1096/fasebj.2021.35.S1.01474

APA Citation style: Richter, K., Ogiemwonyi-Schaefer, R., Wilker, S., Chaveiro, A., Agné, A., Hecker, M., Reichert, M., Amati, A., Schlüter, K., Manzini, I., Schmalzing, G., McIntosh, J., Padberg, W., Grau, V., & Hecker, A. (2021). Amyloid beta peptide (Aβ1–42) antagonizes nicotinic acetylcholine receptors of monocytes and enables ATP-mediated release of interleukin-1β. The FASEB Journal. 35(SI). https://doi.org/10.1096/fasebj.2021.35.S1.01474