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.
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