Tetrapeptide Ac-HAEE-NH2 Protects ?4?2 nAChR from Inhibition by A?.

ABSTRACT: The cholinergic deficit in Alzheimer's disease (AD) may arise from selective loss of cholinergic neurons caused by the binding of A? 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? peptide mediates its interaction with ?4?2 nAChR. This site contains several charged amino acid residues, hence we hypothesized that the formation of A?-?4?2 nAChR complex is based on the interaction of 11EVHH14 with its charge-complementary counterpart in ?4?2 nAChR. Indeed, we discovered a 35HAEE38 site in ?4?2 nAChR, which is charge-complementary to 11EVHH14, and molecular modeling showed that a stable A?42-?4?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? via 11EVHH14 site. Finally, using two-electrode voltage clamp in Xenopus laevis oocytes, we showed that Ac-HAEE-NH2 tetrapeptide completely abolishes the A?42-induced inhibition of ?4?2 nAChR. Thus, we suggest that 35HAEE38 is a potential binding site for A? on ?4?2 nAChR and Ac-HAEE-NH2 tetrapeptide corresponding to this site is a potential therapeutic for the treatment of ?4?2 nAChR-dependent cholinergic dysfunction in AD.

SUBMITTER: Barykin EP 

PROVIDER: S-EPMC7504039 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature