Amyloid Peptide Aβ1-42 Binds Selectively and with Picomolar Affinity to α7 Nicotinic Acetylcholine Receptors

We have recently reported evidence that a very high affinity interaction between the β-amyloid peptide Aβ 1-42 and the a7 nicotinic acetylcholine receptor (α7nAChR) 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 Aβ 1-42 to a7nAChR and α4β2nAChR were determined using the subtypeselective nicotinic receptor ligands [ 3 H]methyllycaconitine and [ 3 H]cytisine. Synaptic membranes prepared from rat and guinea pig cerebral cortex and hippocampus were used as the source of receptors. Aβ 1-42 bound to the a7nAChR 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 a7nAChR, the affinity of Aβ 1-42 for the α4β2nAChR was ∼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 Aβ 1-42 and a7nAChR 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.