Amyloid β1–42 peptide alters the gating of human and mouse α-bungarotoxin-sensitive nicotinic receptors

摘要

The β-amyloid1–42 peptide (Aβ1–42), a major constituent of the Alzheimer's disease amyloid plaque, specifically binds to the neuronal α-bungarotoxin (α-BuTx)-sensitive α7 nicotinic acetylcholine receptor (α7 nAChR). Accordingly, Aβ1–42 interferes with the function of α7 nAChRs in chick and rodent neurons. To gain insights into the human disease, we studied the action of Aβ1–42 on human α7 nAChRs expressed in Xenopus oocytes. In voltage-clamped oocytes expressing the wild-type receptor, Aβ1–42 blocked ACh-evoked currents. The block was non-competitive, required over 100 s to develop and was partially reversible. In oocytes expressing the mutant L248T receptor, Aβ1–42 activated methyllycaconitine-sensitive currents in a dose-dependent manner. Peptide-evoked unitary events, recorded in outside-out patches, showed single-channel conductances and open duration comparable to ACh-evoked events. Aβ1–42 had no effect on the currents evoked by glutamate, GABA or glycine in oocytes expressing human or mouse receptors for these transmitters. Muscle nAChRs are also α-BuTx-sensitive and we therefore investigated whether they respond to Aβ1–42. In human kidney BOSC 23 cells expressing the fetal or adult mouse muscle nAChRs, Aβ1–42 blocked ACh-evoked whole-cell currents, accelerating their decay. Outside-out single-channel recordings showed that the block was due to a reduced channel open probability and enhanced block upon ACh application. We also report that the inverse peptide Aβ42–1, but not Aβ40–1, partially mimicked the effects of the physiological Aβ1–42 peptide. Possible implications for degenerative neuronal and muscular diseases are discussed.