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

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 (IC(50) = 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.