β-amyloid1-42 binds to α7 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 (A beta(1-42)) is involved, Immunohistochemical studies on human sporadic Alzheimer's disease brains demonstrate that A beta(1-42) and a neuronal pentameric cation channel, the alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR), are both present in neuritic plaques and co-localize in individual cortical neurons. Using human brain tissues and cells that overexpress either alpha 7nAChR or amyloid precursor protein as the starting material, A beta(1-42) and alpha 7nAChR can be co-immunoprecipitated by the respective specific antibodies, suggesting that they are tightly associated. The formation of the alpha 7nAChR.A beta(1-42) complex can be efficiently suppressed by AP,,, implying that this AP sequence region contains the binding epitope, Receptor binding experiments show that A beta(1-42) and alpha 7nAChR bind with high affinity, and this interaction can be inhibited by alpha 7nAChR ligands, Human neuroblastoma cells overexpressing alpha 7nAChR are readily killed by A beta(1-42) whereas alpha 7nAChR agonists such as nicotine and epibatidine offered protection. Because A beta(1-42) inhibits alpha 7nAChR-dependent calcium activation and acetylcholine release, two processes critically involved in memory and cognitive functions, and the distribution of alpha 7nAChR correlates with neuritic plaques in Alzheimer's disease brains, we propose that interaction of the alpha 7nAChR and A beta(1-42) is a pivotal mechanism involved in the pathophysiology of Alzheimer's disease.