Peptide blockers of the inhibition of neuronal nicotinic acetylcholine receptors by amyloid β

Alzheimer disease ( AD) is characterized by accumulation of the neurotoxic amyloid beta peptide ( A beta) and by the loss of cholinergic neurons and nicotinic acetylcholine receptors ( nAChRs) throughout the brain. Direct inhibition of nAChRs by A beta has also been suggested to contribute to cholinergic dysfunction in AD. In an effort to find ligands capable of blocking A beta- induced inhibition of nAChRs, we have screened a phage display library to identify peptides that bind to A beta. Using this approach, we identified a heptapeptide denoted IQ, which binds with nanomolar affinity to A beta and is homologous to the acetylcholine- binding protein and to most subtypes of nAChRs. Rapid kinetic whole- cell current- recording measurements showed that A beta inhibits nAChR function in a dose- dependent manner in neuronal differentiated PC12 cells and that nanomolar concentrations of IQ completely block the inhibition by A beta. These results indicate that the A beta binding site in nAChRs is homologous to the IQ peptide and that this is a relevant target for A beta neurotoxicity in AD and, more generally, for the regulation of nAChR function by soluble A beta in a physiological context. Furthermore, the results suggest that the IQ peptide may be a lead for the development of novel drugs to block the inhibition of nAChRs in AD.