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

The cholinergic deficit in Alzheimer&rsquo
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 11EVHH14 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
2 nAChR complex is based on the interaction of 11EVHH14 with its charge-complementary counterpart in &alpha
2 nAChR. Indeed, we discovered a 35HAEE38 site in &alpha
2 nAChR, which is charge-complementary to 11EVHH14, and molecular modeling showed that a stable A&beta
42-&alpha
2 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 A&beta
via 11EVHH14 site. Finally, using two-electrode voltage clamp in Xenopus laevis oocytes, we showed that Ac-HAEE-NH2 tetrapeptide completely abolishes the A&beta
42-induced inhibition of &alpha
2 nAChR. Thus, we suggest that 35HAEE38 is a potential binding site for A&beta
on &alpha
2 nAChR and Ac-HAEE-NH2 tetrapeptide corresponding to this site is a potential therapeutic for the treatment of &alpha
2 nAChR-dependent cholinergic dysfunction in AD.