Amyloid Beta Peptide (Aβ_1-42) Reverses the Cholinergic Control of Monocytic IL-1β Release

• Main Authors: Katrin Richter, Raymond Ogiemwonyi-Schaefer, Sigrid Wilker, Anna I. Chaveiro, Alisa Agné, Matthias Hecker, Martin Reichert, Anca-Laura Amati, Klaus-Dieter Schlüter, Ivan Manzini, Günther Schmalzing, J. Michael McIntosh, Winfried Padberg, Veronika Grau, Andreas Hecker
• Format: Article
• Language: English
• Published: MDPI AG 2020-09-01
• Series: Journal of Clinical Medicine
• Subjects: amyloid beta peptide; interleukin-1β; nicotinic acetylcholine receptors; monocytes; systemic inflammation; purinergic signaling
• Online Access: https://www.mdpi.com/2077-0383/9/9/2887

Amyloid-β peptide (Aβ_1-42), the cleavage product of the evolutionary highly conserved amyloid precursor protein, presumably plays a pathogenic role in Alzheimer’s disease. Aβ_1-42 can induce the secretion of the pro-inflammatory cytokine intereukin-1β (IL-1β) in immune cells within and out of the nervous system. Known interaction partners of Aβ_1-42 are α7 nicotinic acetylcholine receptors (nAChRs). The physiological functions of Aβ_1-42 are, however, not fully understood. Recently, we identified a cholinergic mechanism that controls monocytic release of IL-1β by canonical and non-canonical agonists of nAChRs containing subunits α7, α9, and/or α10. Here, we tested the hypothesis that Aβ_1-42 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 Aβ_1-42. IL-1β concentrations were measured in the supernatant. Aβ_1-42 dose-dependently (IC₅₀ = 2.54 µM) reversed the inhibitory effect of canonical and non-canonical nicotinic agonists on BzATP-mediated IL-1β-release by monocytic cells, whereas reverse Aβ_42-1 was ineffective. In conclusion, we discovered a novel pro-inflammatory Aβ_1-42 function that enables monocytic IL-1β release in the presence of nAChR agonists. These findings provide evidence for a novel physiological function of Aβ_1-42 in the context of sterile systemic inflammation.