Amyloid beta peptide (Aβ _1–42 ) antagonizes nicotinic acetylcholine receptors of monocytes and enables ATP‐mediated release of interleukin‐1β

Abstract

Amyloid‐β peptide (Aβ1‐42) plays a pathogenic role in Alzheimer´s disease. Its physiological functions are, however, still debated. Aβ1‐42 can induce the secretion of the pro‐inflammatory cytokine intereukin‐1β (IL‐1β) by immune cells. Known interaction partners of Aβ1‐42 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 Aβ1‐42 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 Aβ1‐42 was measured by enzyme‐linked immunosorbent assay. We found that Aβ1‐42 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 Aβ1‐42 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 Aβ1‐42 on P2X7 receptor activity was observed. In blood plasma samples from major surgery patients, IL‐1β was mostly detected together with increased Aβ1‐42 levels, which is in line with our hypothesis. Taken together, our results suggest that Aβ1‐42 can antagonize the cholinergic control of ATP‐mediated monocytic IL‐1β‐release and, thus, provide evidence for a novel function of Aβ1‐42 that also might be considered in situations of systemic inflammation.