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

The cholinergic deficit in Alzheimer's disease (AD) may arise from selective loss of cholinergic neurons caused by the binding of A beta peptide to nicotinic acetylcholine receptors (nAChRs). Thus, compounds preventing such an interaction are needed to address the cholinergic dysfunction. Recent findings suggest that the(11)EVHH(14)site in A beta peptide mediates its interaction with alpha 4 beta 2 nAChR. This site contains several charged amino acid residues, hence we hypothesized that the formation of A beta-alpha 4 beta 2 nAChR complex is based on the interaction of(11)EVHH(14)with its charge-complementary counterpart in alpha 4 beta 2 nAChR. Indeed, we discovered a(35)HAEE(38)site in alpha 4 beta 2 nAChR, which is charge-complementary to(11)EVHH(14), and molecular modeling showed that a stable A beta(42)-alpha 4 beta 2 nAChR complex could be formed via the(11)EVHH(14):(35)HAEE(38)interface. Using surface plasmon resonance and bioinformatics approaches, we further showed that a corresponding tetrapeptide Ac-HAEE-NH(2)can bind to A beta via(11)EVHH(14)site. Finally, using two-electrode voltage clamp inXenopus laevisoocytes, we showed that Ac-HAEE-NH(2)tetrapeptide completely abolishes the A beta(42)-induced inhibition of alpha 4 beta 2 nAChR. Thus, we suggest that(35)HAEE(38)is a potential binding site for A beta on alpha 4 beta 2 nAChR and Ac-HAEE-NH(2)tetrapeptide corresponding to this site is a potential therapeutic for the treatment of alpha 4 beta 2 nAChR-dependent cholinergic dysfunction in AD.