Tetrapeptide Ac-HAEE-NH2 Protects α4β2 nAChR from Inhibition by Aβ

Abstract

The cholinergic deficit in Alzheimer’s disease (AD) may arise from selective loss of cholinergic neurons caused by the binding of Aβ peptide to nicotinic acetylcholine receptors (nAChRs). Thus, compounds preventing such an interaction are needed to address the cholinergic dysfunction. Recent findings suggest that the 11EVHH14 site in Aβ peptide mediates its interaction with α4β2 nAChR. This site contains several charged amino acid residues, hence we hypothesized that the formation of Aβ-α4β2 nAChR complex is based on the interaction of 11EVHH14 with its charge-complementary counterpart in α4β2 nAChR. Indeed, we discovered a 35HAEE38 site in α4β2 nAChR, which is charge-complementary to 11EVHH14, and molecular modeling showed that a stable Aβ42-α4β2 nAChR complex could be formed via the 11EVHH14:35HAEE38 interface. Using surface plasmon resonance and bioinformatics approaches, we further showed that a corresponding tetrapeptide Ac-HAEE-NH2 can bind to Aβ via 11EVHH14 site. Finally, using two-electrode voltage clamp in Xenopus laevis oocytes, we showed that Ac-HAEE-NH2 tetrapeptide completely abolishes the Aβ42-induced inhibition of α4β2 nAChR. Thus, we suggest that 35HAEE38 is a potential binding site for Aβ on α4β2 nAChR and Ac-HAEE-NH2 tetrapeptide corresponding to this site is a potential therapeutic for the treatment of α4β2 nAChR-dependent cholinergic dysfunction in AD.

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

“…These findings are consistent with earlier evidence showing that a different core Aβ fragment, Aβ 12-28 , that contains the critical residues of the Aβcore is sufficient to prevent Aβ from binding to α7-nAChRs and reverse Aβ-induced inhibition of α7-nAChRs (44). Finally, a recent study shows that the formation of Aβ-α4β2-nAChRs complex is based on the interaction of a part of Aβcore sequence (EVHH) with α4β2-containing receptors, and blocking this interaction prevents Aβ42-induced inhibition of α4β2-nAChRs (45). This thus suggests interrupting the association of Aβ with nAChRs may be neuroprotective against Aβ-induced neuronal dysfunction in AD, although the differential impact of Aβcore on the three major nAChRs in the hippocampus remains to be explored.…”

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

“…These findings are consistent with earlier evidence showing that a different core Aβ fragment, Aβ 12–28 , that contains the critical residues of the Aβcore is sufficient to prevent Aβ from binding to α7-nAChRs and reverse Aβ-induced inhibition of α7-nAChRs ( 44 ). Finally, a recent study shows that the formation of the Aβ–α4β2-nAChRs complex is based on the interaction of a part of Aβcore sequence (EVHH) with α4β2-containing receptors, and blocking this interaction prevents Aβ42-induced inhibition of α4β2-nAChRs ( 45 ). This thus suggests that interrupting the association of Aβ with nAChRs may be neuroprotective against Aβ-induced neuronal dysfunction in AD, although the differential impact of the Aβcore on the three major nAChRs in the hippocampus remains to be explored.…”

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

“…Since Aβ accumulates in the brain regions enriched in α4β2 nAChRs and α7 nAChRs, the selective vulnerability of the hippocampus to Aβ toxicity can be associated with the high-affinity interaction between Aβ and these nAChRs [ 33 , 34 , 35 , 36 ]. 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 ].…”

“…Such interactions can play a pivotal role in the pathogenesis of AD by initiation of the formation of both neurotoxic Aβ oligomers in biological fluids of the body and extracellular insoluble Aβ aggregates in amyloid plaques characteristic of AD [ 2 ]. It was previously shown that the Aβ site 11-EVHH-14 [ 3 , 4 ] and the site 35-HAEE-38 of the α4 subunit of the α4β2 subtype of nicotinic acetylcholine receptors (α4β2 nAChR) [ 5 ] participate in the Aβ-α4β2 nAChR interaction interface. Synthetic analogs of these sites stabilize the monomeric state of Aβ in vitro and are considered as potential anti-amyloid agents for the treatment of AD [ 6 , 7 ].…”