Alzheimer's disease (AD) is characterized by synaptic dysfunction and cardinal neuropathological features including amyloid plaques and neurofibrillary tangles. Soluble amyloid-β (Aβ) can suppress synaptic activities by interacting with α7 nicotinic acetylcholine receptors (α7nAChRs). Here, we show that α7nAChR and NMDA glutamatergic receptor (NMDAR) activities are severely compromised in synaptosomes prepared from AD and Aβ_1-42 (Aβ₄₂)-exposed control frontal cortex slices from postmortem tissue. Whereas Aβ_12-28 prevents Aβ₄₂ from binding to α7nAChRs, 2-[2-(4-bromophenyl)-2-oxoethyl]-1-methyl pyridinium (S 24795), a novel α7nAChR partial agonist, facilitates release of Aβ₄₂ from Aβ₄₂–α7nAChR and –Aβ₄₂ complexes. S 24795 interacts with α7nAChR and Aβ_15-20 region of the Aβ₄₂ to enable partial recovery of the α7nAChR and NMDAR channel function. These findings suggest that the Aβ–α7nAChR interaction may be an upstream pathogenic event in AD and demonstrate that some recovery of neuronal channel activities may be achieved in AD brains by removing Aβ from α7nAChRs.