Dataset Information

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

ACCESS DATA

Publications

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

Barykin Evgeny P EP Garifulina Aleksandra I AI Tolstova Anna P AP Anashkina Anastasia A AA Adzhubei Alexei A AA Mezentsev Yuri V YV Shelukhina Irina V IV Kozin Sergey A SA Tsetlin Victor I VI Makarov Alexander A AA

International journal of molecular sciences 20200829 17

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 fo ...[more]

PMID: 32872553

Similar Datasets

Project description:Bivalent ligands targeting putative melanocortin receptor dimers have been developed and characterized in vitro; however, studies of their functional in vivo effects have been limited. The current report compares the effects of homobivalent ligand CJL-1-87, Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH2, to monovalent ligand CJL-1-14, Ac-His-DPhe-Arg-Trp-NH2, on energy homeostasis in mice after central intracerebroventricular (ICV) administration into the lateral ventricle of the brain. Bivalent ligand CJL-1-87 had noteworthy advantages as an antiobesity probe over CJL-1-14 in a fasting-refeeding in vivo paradigm. Treatment with CJL-1-87 significantly decreased food intake compared to CJL-1-14 or saline (50% less intake 2-8 h after treatment). Furthermore, CJL-1-87 treatment decreased the respiratory exchange ratio (RER) without changing the energy expenditure indicating that fats were being burned as the primary fuel source. Additionally, CJL-1-87 treatment significantly lowered body fat mass percentage 6 h after administration (p < 0.05) without changing the lean mass percentage. The bivalent ligand significantly decreased insulin, C-peptide, leptin, GIP, and resistin plasma levels compared to levels after CJL-1-14 or saline treatments. Alternatively, ghrelin plasma levels were significantly increased. Serum stability of CJL-1-87 and CJL-1-14 (T1/2 = 6.0 and 16.8 h, respectively) was sufficient to permit physiological effects. The differences in binding affinity of CJL-1-14 compared to CJL-1-87 are speculated as a possible mechanism for the bivalent ligand's unique effects. We also provide in vitro evidence for the formation of a MC3R-MC4R heterodimer complex, for the first time to our knowledge, that may be an unexploited neuronal molecular target. Regardless of the exact mechanism, the advantageous ability of CJL-1-87 compared to CJL-1-14 to increase in vitro binding affinity, increase the duration of action in spite of decreased serum stability, decrease in vivo food intake, decrease mice's body fat percent, and differentially affect mouse hormone levels demonstrates the distinct characteristics achieved from the current melanocortin agonist bivalent design strategy.

Dataset Information

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

Publications

Tetrapeptide Ac-HAEE-NH<sub>2</sub> Protects α4β2 nAChR from Inhibition by Aβ.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets