beta-Amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer's disease pathology.
Alzheimer's disease pathology is characterized by the presence of neuritic plaques and the loss of cholinergic neurons in the brain. The underlying mechanisms leading to these events are unclear, but the 42-amino acid beta-amyloid peptide (Abeta(1-42)) is involved. Immunohistochemical studies on human sporadic Alzheimer's disease brains demonstrate that Abeta(1-42) and a neuronal pentameric cation channel, the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), are both present in neuritic plaques and co-localize in individual cortical neurons. Using human brain tissues and cells that overexpress either alpha7nAChR or amyloid precursor protein as the starting material, Abeta(1-42) and alpha7nAChR can be co-immunoprecipitated by the respective specific antibodies, suggesting that they are tightly associated. The formation of the alpha7nAChR.Abeta(1-42) complex can be efficiently suppressed by Abeta(12-28), implying that this Abeta sequence region contains the binding epitope. Receptor binding experiments show that Abeta(1-42) and alpha7nAChR bind with high affinity, and this interaction can be inhibited by alpha7nAChR ligands. Human neuroblastoma cells overexpressing alpha7nAChR are readily killed by Abeta(1-42), whereas alpha7nAChR agonists such as nicotine and epibatidine offered protection. Because Abeta(1-42) inhibits alpha7nAChR-dependent calcium activation and acetylcholine release, two processes critically involved in memory and cognitive functions, and the distribution of alpha7nAChR correlates with neuritic plaques in Alzheimer's disease brains, we propose that interaction of the alpha7nAChR and Abeta(1-42) is a pivotal mechanism involved in the pathophysiology of Alzheimer's disease.
Wang
H Y
HY
R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477-0776, USA.
Lee
D H
DH
D'Andrea
M R
MR
Peterson
P A
PA
Shank
R P
RP
Reitz
A B
AB
D000109:Acetylcholine / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D016923:Cell Death; D002540:Cerebral Cortex / Q000378:metabolism; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D019004:Galanin / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D018722:Nicotinic Agonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011978:Receptors, Nicotinic / Q000378:metabolism*
D000109:Acetylcholine; D016229:Amyloid beta-Peptides; D002118:Calcium; D016895:Culture Media, Serum-Free; D019004:Galanin; D018722:Nicotinic Agonists; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; C075222:amyloid beta-protein (1-42)