Isomerization of Asp7 in Beta-Amyloid Enhances Inhibition of the α7 Nicotinic Receptor and Promotes Neurotoxicity
Abstract
:1. Introduction
2. Materials and Methods
2.1. Preparation of Aβ Peptides
Synthetic Peptides: Aβ42
2.2. Mouse Neuroblastoma Cell Culture and Transient Transfection
2.3. Radioligand Assay
2.4. Competition Radioligand Assay
2.5. Human Neuroblastoma SH-SY5Y Culture and Differentiation
2.6. Calcium Imaging
2.7. Electrophysiology
2.8. Modelling of Aβ:α7nAChR and Iso-Aβ:α7nAChR Interaction
2.9. Neurotoxicity Measurements
2.10. Statistical Methods Used for Data Analysis
3. Results
3.1. Effects of Aβ42 and Iso-Aβ42 on Functional Activity of α7nAChR in N2a and SH-SY5Y Cells and in Xenopus Laevis Oocytes
3.2. Aβ42 and Iso-Aβ42 Do not Compete with α-Bungarotoxin for Binding to the α7nAChR or to Acetylcholine-Binding Proteins (AChBPs)
3.3. The Aβ42-Induced Reduction of α7nAChR Representation is Neutralized by the Isomerization of Asp7
3.4. Comparison of the Toxicity of Aβ42and Iso-Aβ42 toward SH-SY5Y Cells
3.5. Molecular Modeling of the Binding Sites for Iso-Aβ42 and Aβ42 in the α7nAChR
4. Discussion
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Cell Line | Treatment | EC50 Value, nM |
---|---|---|
N2a | Control | 71.9 ± 8.4 |
Aβ42 | 66.8 ± 8.6 | |
iso-Aβ42 | 112.6 ± 4.3 | |
SH-SY5Y | Control | 114 ± 7.0 |
Aβ42 | 63.4 ± 2.3 | |
iso-Aβ42 | 171 ± 3.3 |
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Barykin, E.P.; Garifulina, A.I.; Kruykova, E.V.; Spirova, E.N.; Anashkina, A.A.; Adzhubei, A.A.; Shelukhina, I.V.; Kasheverov, I.E.; Mitkevich, V.A.; Kozin, S.A.; et al. Isomerization of Asp7 in Beta-Amyloid Enhances Inhibition of the α7 Nicotinic Receptor and Promotes Neurotoxicity. Cells 2019, 8, 771. https://doi.org/10.3390/cells8080771
Barykin EP, Garifulina AI, Kruykova EV, Spirova EN, Anashkina AA, Adzhubei AA, Shelukhina IV, Kasheverov IE, Mitkevich VA, Kozin SA, et al. Isomerization of Asp7 in Beta-Amyloid Enhances Inhibition of the α7 Nicotinic Receptor and Promotes Neurotoxicity. Cells. 2019; 8(8):771. https://doi.org/10.3390/cells8080771
Chicago/Turabian StyleBarykin, Evgeny P., Alexandra I. Garifulina, Elena V. Kruykova, Ekaterina N. Spirova, Anastasia A. Anashkina, Alexei A. Adzhubei, Irina V. Shelukhina, Igor E. Kasheverov, Vladimir A. Mitkevich, Sergey A. Kozin, and et al. 2019. "Isomerization of Asp7 in Beta-Amyloid Enhances Inhibition of the α7 Nicotinic Receptor and Promotes Neurotoxicity" Cells 8, no. 8: 771. https://doi.org/10.3390/cells8080771