Barykin EP , Garifulina AI , Tolstova AP , Anashkina AA , Adzhubei AA , Mezentsev YV , Shelukhina IV , Kozin SA , Tsetlin VI , Makarov AA .

19-74-30007 Russian Science Foundation

             nicotinic acid receptor activity
             cholinergic synapse

	Figure 1. Model of the interaction of the α4β2 nAChR site 35HAEE38 with Aβ42 after 100 ns of molecular dynamics structure equilibration. (A) Model of the α4β2 structure with bound Aβ42 peptide, viewed from the extracellular side. (B) Detailed view of the interaction interface. The Aβ42 peptide is colored green with the 11EVHH14 site shown in cyan. The 35HAEE38 site is colored magenta. The N-terminal α-helix of both α4 and β2 subunits is colored red.
	Figure 2. Global docking of Ac-HAEE-NH2 to Aβ42. (A) A histogram of Aβ42 atomic contacts to the Ac-HAEE-NH2 tetrapeptide for the data from six docking servers. The position of the 11EVHH14 site is highlighted in red. Calculated by QASDOM [20] metaserver. (B,C) Examples of the docked Ac-HAEE-NH2 peptide. The Aβ42 peptide is colored green, with the 11EVHH14 site shown in cyan, and the Ac-HAEE-NH2 tetrapeptide is colored magenta.
	Figure 3. Sensorgrams showing direct binding of Ac-HAEE-NH2 (1 mM–2 mM) to immobilized Aβ16. Spikes at the start and end of Ac-HAEE-NH2 injections are due to a slight time delay in the reference cell and appear when reference subtraction is carried out.
	Figure 4. Global docking of Ac-HAEE-NH2 to Aβ16 (A,B) Examples of the docked Ac-HAEE-NH2 peptide. The Aβ16 peptide is colored green with the 11EVHH14 site shown in cyan, and the Ac-HAEE-NH2 tetrapeptide is colored magenta. (C) The proposed interface of HAEE-EVHH interaction based on a docking model.
	Figure 5. (A) Representative ion current traces and (B) normalized amplitudes of ACh (100 μM)-induced ion currents in α4β2 nAChR-expressing Xenopus laevis oocytes in control and after 3 min pre-incubation with 10 µM Aβ42 (“Aβ42”), 10 µM Aβ42 and 100 µM Ac-HAEE-NH2 (“HAEE + Aβ42”), or 10 µM Aβ42 followed by washout with Barth’s solution containing 100 µM of Ac-HAEE-NH2 (“HAEE after Aβ42”). (B) Individual current amplitude values are depicted as black dots. (C) Normalized ACh (100 μM)-induced current amplitudes in α4β2 nAChR-expressing Xenopus laevis oocytes in control and after 3 min pre-incubation with 10 µM Aβ42, followed by 3 min washout with Barths’ solution in the absence (“Aβ42”) or presence (“HAEE”) of Ac-HAEE-NH2. (A,C) Data are presented as mean ± SD, n ≥ 3. *—p < 0.05, **—p < 0.005, ***—p < 0.001, ****—p < 0.0001, ns—nonsignificant. (D) The leakage current in α4β2 nAChR-expressing Xenopus laevis oocytes was measured after 3 min consecutive incubations in Barth’s solution (“Barth”), in Barth’s solution containing 10 µM Aβ42 (“Aβ42”), and in Barth’s solution in the absence (“Barth”) and presence of 100 µM Ac-HAEE-NH2 (“HAEE”).
	Figure 6. The possible role of 11EVHH14:35HAEE38 interface in cholinergic deficit associated with Alzheimer’s disease. In brains of Alzheimer’s disease patients, interaction of Aβ with nAChRs causes transition of the receptor from functional state (green) to dysfunctional state (violet), which may lead to selective loss of cholinergic neurons (top left). Our results suggest that the interaction of Aβ with α4β2 nAChR is mediated by charge complementary interface 11EVHH14:35HAEE38 (bottom left and middle) and that Ac-HAEE-NH2 peptide corresponding to this interface can competitively displace Aβ from the complex and restore the functionality of α4β2 nAChR (top right).

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