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Quantitative assessment of oligomeric amyloid ? peptide binding to ?7 nicotinic receptor.

ABSTRACT: BACKGROUND AND PURPOSE:Progressive dysfunction of cholinergic transmission is a well-known characteristic of Alzheimer's disease (AD). Amyloid ? (A?) peptide oligomers are known to play a central role in AD and are suggested to impair the function of the cholinergic nicotinic ACh receptor ?7 (?7nAChR). However, the mechanism underlying the effect of A? on ?7nAChR function is not fully understood, limiting the therapeutic exploration of this observation in AD. Here, we aimed to detect and characterize A? binding to ?7nAChR, including the possibility of interfering with this interaction for therapeutic purposes. EXPERIMENTAL APPROACH:We developed a specific and quantitative time-resolved FRET (TR-FRET)-based binding assay for A? to ?7nAChR and pharmacologically characterized this interaction. KEY RESULTS:We demonstrated specific and high-affinity (low nanomolar) binding of A? to the orthosteric binding site of ?7nAChR. A? binding was prevented and reversed by the well-characterized orthosteric ligands of ?7nAChR (epibatidine, ?-bungarotoxin, methylylcaconitine, PNU-282987, S24795, and EVP6124) and by the type II positive allosteric modulator (PAM) PNU-120596 but not by the type I PAM NS1738. CONCLUSIONS AND IMPLICATIONS:Our TR-FRET A? binding assay demonstrates for the first time the specific binding of A? to ?7nAChR, which will be a crucial tool for the development, testing, and selection of a novel generation of AD drug candidates targeting A?/?7nAChR complexes with high specificity and fewer side effects compared to currently approved ?7nAChR drugs. LINKED ARTICLES:This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

SUBMITTER: Cecon E

PROVIDER: S-EPMC6715828 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor.

Cecon Erika E Dam Julie J Luka Marine M Gautier Clément C Chollet Anne-Marie AM Delagrange Philippe P Danober Laurence L Jockers Ralf R

British journal of pharmacology 20190520 18

<h4>Background and purpose</h4>Progressive dysfunction of cholinergic transmission is a well-known characteristic of Alzheimer's disease (AD). Amyloid β (Aβ) peptide oligomers are known to play a central role in AD and are suggested to impair the function of the cholinergic nicotinic ACh receptor α7 (α7nAChR). However, the mechanism underlying the effect of Aβ on α7nAChR function is not fully understood, limiting the therapeutic exploration of this observation in AD. Here, we aimed to detect and ...[more]

PMID: 30981214

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Project description:Alzheimer's disease and Type 2 diabetes are pathological processes associated to ageing. Moreover, there are evidences supporting a mechanistic link between Alzheimer's disease and insulin resistance (one of the first hallmarks of Type 2 diabetes). Regarding Alzheimer's disease, amyloid β-peptide aggregation into β-sheets is the main hallmark of Alzheimer's disease. At monomeric state, amyloid β-peptide is not toxic but its function in brain, if any, is unknown. Here we show, by in silico study, that monomeric amyloid β-peptide 1-40 shares the tertiary structure with insulin and is thereby able to bind and activate insulin receptor. We validated this prediction experimentally by treating human neuroblastoma cells with increasing concentrations of monomeric amyloid β-peptide 1-40. Our results confirm that monomeric amyloid β-peptide 1-40 activates insulin receptor autophosphorylation, triggering downstream enzyme phosphorylations and the glucose Transporter 4 translocation to the membrane. On the other hand, neuronal insulin resistance is known to be associated to Alzheimer's disease since early stages. We thus modelled the docking of oligomeric amyloid β-peptide 1-40 to insulin receptor. We found that oligomeric amyloid β-peptide 1-40 blocks insulin receptor, impairing its activation. It was confirmed in vitro by observing the lack of insulin receptor autophosphorylation, and also the impairment of insulin-induced intracellular enzyme activations and the glucose Transporter 4 translocation to the membrane. By biological system analysis, we have carried out a mathematical model recapitulating the process that turns amyloid β-peptide binding to insulin receptor from the physiological to the pathophysiological regime. Our results suggest that monomeric amyloid β-peptide 1-40 contributes to mimic insulin effects in the brain, which could be good when neurons have an extra requirement of energy beside the well-known protective effects on insulin intracellular signalling, while its accumulation and subsequent oligomerization blocks the insulin receptor producing insulin resistance and compromising neuronal metabolism and protective pathways.

Dataset Information

Quantitative assessment of oligomeric amyloid ? peptide binding to ?7 nicotinic receptor.

Publications

Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor.

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