Dissociating β-Amyloid from α7 Nicotinic Acetylcholine Receptor by a Novel Therapeutic Agent, S 24795, Normalizes α7 Nicotinic Acetylcholine and NMDA Receptor Function in Alzheimer's Disease Brain (Publication with Expression of Concern)

Alzheimer's disease (AD) is characterized by synaptic dysfunction and cardinal neuropathological features including amyloid plaques and neurofibrillary tangles. Soluble amyloid-beta (A beta) can suppress synaptic activities by interacting with alpha 7 nicotinic acetylcholine receptors (alpha 7nAChRs). Here, we show that alpha 7nAChR and NMDA glutamatergic receptor (NMDAR) activities are severely compromised in synaptosomes prepared from AD and A beta(1-42) (A beta(42))-exposed control frontal cortex slices from postmortem tissue. Whereas A beta(12-28) prevents A beta(42) from binding to alpha 7nAChRs, 2-[2-(4-bromophenyl)-2-oxoethyl]-1-methyl pyridinium (S 24795), a novel alpha 7nAChR partial agonist, facilitates release of A beta(42) from A beta(42)-alpha 7nAChR and -A beta(42) complexes. S 24795 interacts with alpha 7nAChR and A beta(15-20) region of the A beta(42) to enable partial recovery of the alpha 7nAChR and NMDAR channel function. These findings suggest that the A beta-alpha 7nAChR 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 A beta from alpha 7nAChRs.