β-Amyloid1–42 Binds to α7 Nicotinic Acetylcholine Receptor with High Affinity

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 β-amyloid peptide (Aβ1–42) is involved. Immunohistochemical studies on human sporadic Alzheimer's disease brains demonstrate that Aβ1–42 and a neuronal pentameric cation channel, the α7 nicotinic acetylcholine receptor (α7nAChR), are both present in neuritic plaques and co-localize in individual cortical neurons. Using human brain tissues and cells that overexpress either α7nAChR or amyloid precursor protein as the starting material, Aβ1–42 and α7nAChR can be co-immunoprecipitated by the respective specific antibodies, suggesting that they are tightly associated. The formation of the α7nAChR·Aβ1–42complex can be efficiently suppressed by Aβ12–28, implying that this Aβ sequence region contains the binding epitope. Receptor binding experiments show that Aβ1–42 and α7nAChR bind with high affinity, and this interaction can be inhibited by α7nAChR ligands. Human neuroblastoma cells overexpressing α7nAChR are readily killed by Aβ1–42, whereas α7nAChR agonists such as nicotine and epibatidine offered protection. Because Aβ1–42 inhibits α7nAChR-dependent calcium activation and acetylcholine release, two processes critically involved in memory and cognitive functions, and the distribution of α7nAChR correlates with neuritic plaques in Alzheimer's disease brains, we propose that interaction of the α7nAChR and Aβ1–42 is a pivotal mechanism involved in the pathophysiology of Alzheimer's disease.