Selective coactivation of α7-and α4β2-nicotinic acetylcholine receptors reverses beta-amyloid-induced synaptic dysfunction

Beta-amyloid (A beta) has been recognized as an early trigger in the pathogenesis of Alzheimer's disease (AD) leading to synaptic and cognitive impairments. A beta can alter neuronal signaling through interactions with nicotinic acetylcholine receptors (nAChRs), contributing to synaptic dysfunction in AD. The three major nAChR subtypes in the hippocampus are composed of alpha 7-, alpha 4 beta 2-, and alpha 3 beta 4-nAChRs. A beta selectively affects alpha 7- and alpha 4 beta 2-nAChRs, but not alpha 3 beta 4-nAChRs in hippocampal neurons, resulting in neuronal hyperexcitation. However, how nAChR subtype selectivity for A beta affects synaptic function in AD is not completely understood. Here, we showed that A beta associated with alpha 7- and alpha 4 beta 2-nAChRs but not alpha 3 beta 4-nAChRs. Computational modeling suggested that two amino acids in alpha 7-nAChRs, arginine 208 and glutamate 211, were important for the interaction between A beta and alpha 7-containing nAChRs. These residues are conserved only in the alpha 7 and alpha 4 subunits. We therefore mutated these amino acids in alpha 7-containing nAChRs to mimic the alpha 3 subunit and found that mutant alpha 7-containing receptors were unable to interact with A beta. In addition, mutant alpha 3-containing nAChRs mimicking the alpha 7 subunit interact with A beta. This provides direct molecular evidence for how A beta selectively interacted with alpha 7- and alpha 4 beta 2-nAChRs, but not alpha 3 beta 4-nAChRs. Selective coactivation of alpha 7- and alpha 4 beta 2-nAChRs also sufficiently reversed A beta-induced AMPA receptor dysfunction, including A beta-induced reduction of AMPA receptor phosphorylation and surface expression in hippocampal neurons. Moreover, costimulation of alpha 7- and alpha 4 beta 2-nAChRs reversed the A beta-induced disruption of long-term potentiation. These findings support a novel mechanism for A beta's impact on synaptic function in AD, namely, the differential regulation of nAChR subtypes.