Amyloid Beta Peptide (A?1-42) Reverses the Cholinergic Control of Monocytic IL-1? Release.

ABSTRACT: Amyloid-? peptide (A?1-42), the cleavage product of the evolutionary highly conserved amyloid precursor protein, presumably plays a pathogenic role in Alzheimer's disease. A?1-42 can induce the secretion of the pro-inflammatory cytokine intereukin-1? (IL-1?) in immune cells within and out of the nervous system. Known interaction partners of A?1-42 are ?7 nicotinic acetylcholine receptors (nAChRs). The physiological functions of A?1-42 are, however, not fully understood. Recently, we identified a cholinergic mechanism that controls monocytic release of IL-1? by canonical and non-canonical agonists of nAChRs containing subunits ?7, ?9, and/or ?10. Here, we tested the hypothesis that A?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 A?1-42. IL-1? concentrations were measured in the supernatant. A?1-42 dose-dependently (IC50 = 2.54 µM) reversed the inhibitory effect of canonical and non-canonical nicotinic agonists on BzATP-mediated IL-1?-release by monocytic cells, whereas reverse A?42-1 was ineffective. In conclusion, we discovered a novel pro-inflammatory A?1-42 function that enables monocytic IL-1? release in the presence of nAChR agonists. These findings provide evidence for a novel physiological function of A?1-42 in the context of sterile systemic inflammation.

SUBMITTER: Richter K 

PROVIDER: S-EPMC7564705 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature