Selective coactivation 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 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 that two amino acids in α7-nAChRs, arginine 208 and glutamate 211, 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. In addition, 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 coactivation of α7- and α4β2-nAChRs also sufficiently reversed Aβ-induced AMPA receptor dysfunction, including Aβ-induced reduction of AMPA receptor phosphorylation and surface expression in hippocampal neurons. Moreover, costimulation 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.

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

“…To identify the binding site for Aβ 42, 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 Aβ 42 binding [20]. Therefore, we concluded that the amyloid β (Aβ42) binding site overlaps with that for α-BTX.…”

“…For Aβ 42 interactions, the ligand residues that interacted with the receptor binding sites were located in the C-terminal regions of the Aβ 42 monomer (Table 2). The predicted binding affinity of the Aβ 42 to the binding site comprising two α7 subunits (the canonical receptor) was in the low nM range, consistent with available experimental data [20]. 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. Aβ 42 and α7 interact with high affinity [19,20]. However, the details of those interactions remain elusive.…”

Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood–Brain Barrier

“…The Aβ–α4β2 nAChR interaction interface is formed by the 11-EVHH-14 and 35-HAEE-38 sites of Aβ and the α4 subunit of α4β2 nAChR, respectively [ 5 ]. The 11-EVHH-14 region of Aβ also plays a critical role in Aβ binding to α7 nAChRs; however, the exact interface of the Aβ-α7 nAChR complex is unknown [ 4 , 6 , 29 , 37 , 38 ]. The 11-EVHH-14 region has a relatively rigid backbone conformation in soluble Aβ monomers [ 39 , 40 ] and zinc-bound dimers [ 41 ].…”

Dementia model mice exhibited improvements of neuropsychiatric symptoms as well as cognitive dysfunction with neural cell transplantation

“…ACh acts via two classes of receptors: ionotropic nicotinic receptors (nAChRs) and metabotropic muscarinic receptors (mAChRs). The major subtypes of nAChRs, nAChRα7 and nAChRα4β2 regulate synaptic plasticity [ 12 ]. The activity of cholinergic neurons and ACh production by cholinergic neurons decrease in AD patients, and administration of anticholinergic drugs is associated with the development of AD [ 13 , 14 ].…”