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 EVHH 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 EVHH with its charge-complementary counterpart in α4β2 nAChR. Indeed, we discovered a HAEE site in α4β2 nAChR, which is charge-complementary to EVHH, and molecular modeling showed that a stable Aβ-α4β2 nAChR complex could be formed via the EVHH:HAEE interface. Using surface plasmon resonance and bioinformatics approaches, we further showed that a corresponding tetrapeptide Ac-HAEE-NH can bind to Aβ via EVHH site. Finally, using two-electrode voltage clamp in oocytes, we showed that Ac-HAEE-NH tetrapeptide completely abolishes the Aβ-induced inhibition of α4β2 nAChR. Thus, we suggest that HAEE is a potential binding site for Aβ on α4β2 nAChR and Ac-HAEE-NH tetrapeptide corresponding to this site is a potential therapeutic for the treatment of α4β2 nAChR-dependent cholinergic dysfunction in AD.