Amyloid peptide Abeta(1-42) binds selectively and with picomolar affinity to alpha7 nicotinic acetylcholine receptors.
We have recently reported evidence that a very high affinity interaction between the beta-amyloid peptide Abeta(1-42) and the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) 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 Abeta(1-42) to alpha7nAChR and alpha4beta2nAChR were determined using the subtype-selective 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. Abeta(1-42) bound to the alpha7nAChR 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 alpha7nAChR, the affinity of Abeta(1-42) for the alpha4beta2nAChR was approximately 5,000-fold lower, as indicated by corresponding K(i) values of 30 and 23nM. The results of this study support the concept that an exceptionally high affinity interaction between Abeta(1-42) and alpha7nAChR 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.
R. W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477-0776, USA. hwang2@prius.jnj.com
H Y
HY
Wang
D H
DH
Lee
C B
CB
Davis
R P
RP
Shank
D000157:Aconitine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000470:Alkaloids / Q000493:pharmacokinetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001392:Azocines; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism*; D006168:Guinea Pigs; D006624:Hippocampus / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D009538:Nicotine / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000378:metabolism*; D011807:Quinolizines; D011869:Radioligand Assay; D051381:Rats; D020318:Rats, Long-Evans; D011976:Receptors, Muscarinic / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013570:Synaptic Membranes / Q000378:metabolism*; D014316:Tritium; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000093843:Quinolizidine Alkaloids
D000157:Aconitine; D000470:Alkaloids; D016229:Amyloid beta-Peptides; D001392:Azocines; D009538:Nicotine; D010446:Peptide Fragments; D011807:Quinolizines; D011976:Receptors, Muscarinic; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D014316:Tritium; D064569:alpha7 Nicotinic Acetylcholine Receptor; C579165:Chrna7 protein, rat; C075222:amyloid beta-protein (1-42); C054634:methyllycaconitine; C004712:cytisine; D000093843:Quinolizidine Alkaloids