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

Abstract

Beta-amyloid (Aβ) has been recognized as an early trigger in the pathogenesis of Alzheimers 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. A selectively affects α7- and α4β2-nAChRs, but not α3β4-nAChRs in hippocampal neurons, resulting inneuronal 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.

Structure, Dynamics, and Ligand Recognition of Human-Specific CHRFAM7A (Dupα7) Nicotinic Receptor Linked to Neuropsychiatric Disorders

“…To identify the binding site for Aβ42, we performed the exhaustive scan of the whole extracellular receptor domain using ClusPro. The best-scoring poses (8/10) converged to the site, which partially overlaps with the reported α-BTX binding sites, consistent with the reports on α7 receptor activation via orthosteric modality reversing the Aβ42 binding (Roberts et al, 2021). Therefore, we concluded that the amyloid β (Aβ42) binding site overlaps with that for α-BTX.…”

“…For Aβ42 interactions, the ligand residues that interacted with the receptor binding sites were located in the C-terminal regions of the Aβ42 monomer ( Table 2). The predicted binding affinity of the Aβ42 to the binding site comprising two α7 subunits (the canonical receptor) was in the low nM range, consistent with available experimental data (Roberts et al, 2021). As a comparison, α-BTX was predicted to bind to the canonical a7 binding sites with one order of magnitude lower (high pM range) than Aβ.…”

“…While the experimental structure of α-BTX-α7 is known (PDB code: 4HQP), the structural information on interactions between receptors containing Dupα7 subunits and α-BTX is missing. Aβ42 and α7 interact with high affinity (Ihnatovych et al, 2019;Roberts et al, 2021). However, the details of those interactions remain elusive.…”

Structure, Dynamics, and Ligand Recognition of Human-Specific CHRFAM7A (Dupα7) Nicotinic Receptor Linked to Neuropsychiatric Disorders

“…While the experimental structure of α-BTX-α7 is known (PDB code: 4HQP), the structural information on interactions between receptors containing Dupα7 subunits and α-BTX is missing. Aβ 42 and α7 interact with high affinity [ 19 , 20 ]. However, the details of those interactions remain elusive.…”

The Mechanism by Which LiCl Attenuates the Impaired Ability of Learning and Memory of APP/PS1 Double Transgenic Mice May Involve Elevating the Expression of a7 Nicotinic Acetylcholine Receptors via Regulation of the Wnt/β-catenin Pathway

“…Aβ damages nAChRs, and in particular α7 nAChR, directly, thereby altering neuronal signaling and contributing to the synaptic dysfunction associated with AD. Computational modeling indicates that arginine-208 and glutamate-211 in α7 nAChR are involved in their interaction with Aβ [65].…”