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

Beta-amyloid (Aβ) has been recognized as an early trigger in the pathogenesis of Alzheimer’s disease (AD) leading to synaptic and cognitive impairments. Aβ 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 α7-, α4β2-, and α3β4-nAChRs. Aβ selectively affects α7- and α4β2-nAChRs, but not α3β4-nAChRs in hippocampal neurons, resulting in neuronal hyperexcitation. However, how nAChR subtype selectivity for Aβ affects synaptic function in AD is not completely understood. Here, we showed that Aβ associated with α7- and α4-containing nAChRs but not α3-containing receptors. Computational modeling suggested two amino acids in α7-nAChRs, Arginine 208 and Glutamate 211, were important for the interaction between Aβ and α7-containing nAChRs. These residues were found to be conserved only in the α7 and α4 subunits. We therefore mutated these amino acids in α7-containing nAChRs to mimic the α3 subunit and found that mutant α7-containing receptors were unable to interact with Aβ, providing direct molecular evidence for how Aβ selectively interacted with α7- and α4-containing receptors, but not α3-containing nAChRs. Selective co-activation of α7- and α4β2-nAChRs was also sufficient to reverse Aβ-induced AMPA receptor (AMPAR) dysfunction, including Aβ-induced reduction of AMPAR phosphorylation and surface expression in hippocampal neurons. Moreover, the Aβ-induced disruption of long-term potentiation was reversed by co-stimulation of α7- and α4β2-nAChRs. These findings support a novel mechanism for Aβ’s impact on synaptic function in AD, namely the differential regulation of nAChR subtypes.