(R3027) Selective Co-activation of α7 and α4β2 Nicotinic Acetylcholine Receptors Reverses Beta-amyloid-induced Synaptic Dysfunction Jessica P. Roberts1,2,4, Sarah A. Stokoe1,2,4, Matheus F. Sathler2, Robert A. Nichols3, Seonil Kim1,2 1Molecular, Cellular and Integrative Neurosciences Program 2Department of Biomedical Sciences, Colorado State University, CO, 80523 3Department of Cell and Molecular Biology, University of Hawai`i at Manoa, Honolulu, HI, 96813 4These authors contribute equally

Jessica Roberts (Colorado State University)

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 α4β2-nAChRs but not α3β4-nAChRs. Computational modeling suggested two amino acids in α7-nAChRs, arginine (R208) and glutamate (E211), were important for the interaction between Aβ and α7-containing nAChRs. These residues are 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. Additionally, mutant α3-containing nAChRs mimicking the α7 subunit interact with Aβ. This provides direct molecular evidence for how Aβ selectively interacted with α7- and α4β2-nAChRs, but not α3β4-nAChRs. Selective co-activation of α7- and α4β2-nAChRs also sufficiently reversed Aβ-induced AMPA receptor (AMPAR) dysfunction, including Aβ-induced reduction of AMPAR phosphorylation and surface expression in hippocampal neurons. Moreover, co-stimulation of α7- and α4β2-nAChRs reversed the Aβ-induced disruption of long-term potentiation. These findings support a novel mechanism for Aβ’s impact on synaptic function in AD, namely the differential regulation of nAChR subtypes.

Support or Funding Information

This work is supported by the University of Hawai'i Foundation Preclinical Alzheimer's Research Fund (RAN), the pilot program from the Colorado Clinical and Translational Sciences Institute (SK), College Research Council Shared Research Program from Colorado State University (SK), the Boettcher Foundation (SK), The Barry Goldwater Scholarship and Excellence in Education Foundation (JPR), Astronaut Scholarship Foundation (JPR), and Student Experiential Learning Grant from Colorado State University (JPR and SAS).