Amyloid peptide A beta(1-42) binds selectively and with picomolar affinity to alpha 7 nicotinic acetylcholine receptors

We have recently reported evidence that a very high affinity interaction between the beta-amyloid peptide A beta(1-42) and the alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) may be a precipitating event in the formation of amyloid plaques in Alzheimer's disease. In the present study, the kinetics for the binding of A beta(1-42) to alpha 7nAChR and alpha 4 beta 2nAChR were determined using the subtype-selective nicotinic receptor ligands [H-3]methyllycaconitine and [H-3]cytisine. Synaptic membranes prepared from rat and guinea pig cerebral cortex and hippocampus were used as the source of receptors, A beta(1-42) bound to the alpha 7nAChR with exceptionally high affinity, as indicated by K-i values of 4.1 and 5.0 pM for rat and guinea pig receptors, respectively. When compared with the alpha 7nAChR, the affinity of A beta(1-42) for the alpha 4 beta 2nAChR was similar to 5,000-fold lower, as indicated by corresponding K-i values of 30 and 23 nM, The results of this study support the concept that an exceptionally high affinity interaction between A beta(1-42) and alpha 7nAChR could serve as a precipitating factor in the formation of amyloid plaques and thereby contribute to the selective degeneration of cholinergic neurons that originate in the basal forebrain and project to the cortex and hippocampus.