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.