Isomerization of Asp7 in Beta-Amyloid Enhances Inhibition of the α7 Nicotinic Receptor and Promotes Neurotoxicity

Abstract

Cholinergic dysfunction in Alzheimer’s disease (AD) can be mediated by the neuronal α7 nicotinic acetylcholine receptor (α7nAChR). Beta-amyloid peptide (Aβ) binds to the α7nAChR, disrupting the receptor’s function and causing neurotoxicity. In vivo not only Aβ but also its modified forms can drive AD pathogenesis. One of these forms, iso-Aβ (containing an isomerized Asp7 residue), shows an increased neurotoxicity in vitro and stimulates amyloidogenesis in vivo. We suggested that such effects of iso-Aβ are α7nAChR-dependent. Here, using calcium imaging and electrophysiology, we found that iso-Aβ is a more potent inhibitor of the α7nAChR-mediated calcium current than unmodified Aβ. However, Asp7 isomerization eliminated the ability of Aβ to decrease the α7nAChR levels. These data indicate differences in the interaction of the peptides with the α7nAChR, which we demonstrated using computer modeling. Neither Aβ nor iso-Aβ competed with 125I-α-bungarotoxin for binding to the orthosteric site of the receptor, suggesting the allosteric binging mode of the peptides. Further we found that increased neurotoxicity of iso-Aβ was mediated by the α7nAChR. Thus, the isomerization of Asp7 enhances the inhibitory effect of Aβ on the functional activity of the α7nAChR, which may be an important factor in the disruption of the cholinergic system in AD.

Amyloid Beta Peptide (Aβ1-42) Reverses the Cholinergic Control of Monocytic IL-1β Release

“…Ample evidence suggests that amyloid precursor protein (APP) and its cleavage products interfere with the cholinergic system. The α7 nAChR subunits are direct interaction partners for Aβ peptides [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Therefore, we decided to investigate the interaction between APP, nAChRs, and the IL-1β system.…”

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

“…However, the data concerning the effects exerted by Aβ on nAChRs are contradictory, with some authors showing the activation of the receptor, while the others show the suppression of the receptor function [ 31 ]. The interaction site remains unclear, and previous findings support both the orthosteric [ 32 ] and the allosteric [ 7 , 33 , 34 ] binding to nAChRs. Molecular modelling of Aβ-nAChR interaction is also complicated due to the absence of complete or well-resolved (<3 Å) receptor structures, however, a few models of Aβ-α7 nAChR complexes were created with bioinformatics approaches [ 7 , 35 , 36 ].…”

“…For this, we used a two-electrode voltage clamp in X. laevis oocytes expressing α4β2 nAChR from Rattus norvegicus . This technique was intensively used in our previous projects to study effects on nAChRs of peptide ligands, including those produced by Aβ peptides [ 7 , 55 , 56 ]. Rat and human α4β2 nAChRs share high homology with the full conservation of “HAEE” site at the N-termini of α4 subunit.…”

“…For a long period, the concepts of AD molecular pathology were focused on the role of amyloid plaques; however, it is becoming clear that neurotoxic oligomers of β-amyloid (Aβ) should be targeted as well [ 1 , 3 , 4 , 5 ]. Soluble neurotoxic Aβ species interact with different targets, resulting in a systemic impairment of neuronal and glial function [ 4 , 6 , 7 ]. Important targets of Aβ are brain nicotinic acetylcholine receptors (nAChRs).…”

Activation of α7 Nicotinic Acetylcholine Receptor Upregulates HLA-DR and Macrophage Receptors: Potential Role in Adaptive Immunity and in Preventing Immunosuppression

“…This effect became more prominent after application of more potent agonist epibatidine (Epi, 10 µM, Figure 3B,K) and α7 nAChR selective agonist PNU 282,987 (1 µ M, Figure 3C,K). It is very hard or even impossible to detect α7 nAChR-mediated calcium response in neurons and neuroblastoma cells in the absence of a selective positive α7 nAChR allosteric modulator PNU 120,596, decreasing the extremely high rate of receptor desensitization [35][36][37]. Applying PNU 120,596 (10µ M) to THP-1ϕ cells, we observed a great increase in the number of nicotine-responsive cells and in the corresponding calcium rise amplitudes ( Figure 3D,L).…”