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 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.