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

We have recently reported evidence that a very high affinity interaction be tween the beta-amyloid peptide A beta(1-42) and the alpha 7 nicotinic acety lcholine receptor (alpha 7nAChR) may be a precipitating event in the format ion of amyloid plaques in Alzheimer's disease. In the present study, the ki netics for the binding of A beta(1-42) to alpha 7nAChR and alpha 4 beta 2nA ChR 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 hi gh affinity, as indicated by K-i values of 4.1 and 5.0 pM for rat and guine a pig receptors, respectively. When compared with the alpha 7nAChR, the aff inity 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 resul ts of this study support the concept that an exceptionally high affinity in teraction between A beta(1-42) and alpha 7nAChR could serve as a precipitat ing factor in the formation of amyloid plaques and thereby contribute to th e selective degeneration of cholinergic neurons that originate in the basal forebrain and project to the cortex and hippocampus.