Interaction Between Glucagon-like Peptide 1 and Its Analogs with Amyloid-β Peptide Affects Its Fibrillation and Cytotoxicity
Abstract
1. Introduction
2. Results
2.1. Interaction Between GLP-1RAs and Monomeric Aβ
2.2. Concentration-Dependent Changes in Quaternary Structure of GLP-1RAs
2.3. Effect of GLP-1RAs on Aβ Fibrillation
2.4. Structural Modeling of Complexes Between Aβ40 or Its Protofibril and GLP-1(7-37)/Exen
2.5. Effect of GLP-1RAs on Aβ Cytotoxicity Toward Human Neuroblastoma Cells
3. Materials and Methods
3.1. Materials
3.2. BLI Measurements
3.3. SPR Measurements
3.4. Dynamic Light Scattering Measurements
3.5. Structural Modeling
3.6. ThT Fluorescence Assay
3.7. Transmission Electron Microscopy
3.8. Cell Viability Assay
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
2-ME | 2-mercaptoethanol |
Aβ | amyloid-β peptide |
Aβ40/Aβ42 | amyloid-β peptide, residues 1-40/42 |
AD | Alzheimer’s disease |
APP | amyloid precursor protein |
BBB | blood–brain barrier |
CNS | central nervous system |
DM | diabetes mellitus |
DM2 | type 2 diabetes mellitus |
DMEM | Dulbecco’s Modified Eagle Medium |
DMSO | dimethyl sulfoxide |
DPP-4 | dipeptidyl peptidase-4 |
EDAC/sulfo-NHS | 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride/N-hydroxysulfosuccinimide |
EDTA | ethylenediaminetetraacetic acid |
EM | electron microscope |
Exen | exendin-4/exenatide |
GLP-1 | glucagon-like peptide 1 |
GLP-1(7-36), GLP-1(7-37) | N-terminally truncated forms of glucagon-like peptide 1, residues 7-36 or 7-37 |
GLP-1R | glucagon-like peptide 1 receptor |
GLP-1RA | glucagon-like peptide 1 receptor agonist |
HSA | human serum albumin |
Lira | liraglutide |
MTT | 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide |
MWm | molecular mass calculated from the amino acid sequence |
MWRh | molecular mass calculated from the hydrodynamic radius |
NMR | nuclear magnetic resonance |
PA | palmitic acid |
PDB | Protein Data Bank |
Sema | semaglutide |
SDS | sodium dodecyl sulfate |
TEM | transmission electron microscopy |
TFA | trifluoroacetic acid |
ThT | thioflavin T |
Tris | tris(hydroxymethyl)aminomethane |
TWEEN | polyethylene glycol sorbitan monolaurate |
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[Lira], µM | ka, M−1s−1 | kd, s−1 | KD, M | ka, M−1s−1 | kd, s−1 | KD, M | |
Lira | Aβ40 | Aβ42 | |||||
20 | (8.4 ± 2.8) × 103 | (9.0 ± 0.4) × 10−4 | (1.1 ± 0.4) × 10−7 | (5.7 ± 1.1) × 103 | (6.0 ± 0.2) × 10−4 | (1.1 ± 0.2) × 10−7 | |
10 | (7.3 ± 0.4) × 103 | (3.46 ± 0.07) × 10−4 | (4.8± 0.3) ×10−8 | (8.0 ± 0.7) × 103 | (4.82 ± 0.12) × 10−4 | (6.0 ± 0.2) × 10−8 | |
5 | (1.34 ± 0.09) × 104 | (5.56 ± 0.11) × 10−4 | (4.2 ± 0.3) × 10−8 | (1.21 ± 0.08) × 104 | (5.40 ± 0.12) × 10−4 | (4.5 ± 0.3) × 10−8 | |
[Sema], µM | ka1, M−1s−1 | kd1, s−1 | KD1, M | ka2, M−1s−1 | kd2, s−1 | KD2, M | |
Sema | Aβ40 | ||||||
17 | 310 ± 52 | (3.7 ± 0.2) × 10−3 | (1.2 ± 0.2) × 10−5 | (5.7 ± 1.1) × 103 | (9.1 ± 0.6) × 10−2 | (1.6 ± 0.3) × 10−5 | |
Aβ42 | |||||||
38 | 582 ± 104 | (6.4 ± 0.6) × 10−3 | (1.1 ± 0.2) × 10−5 | (6.1 ± 2.7) × 103 | (1.34 ± 0.15) × 10−1 | (2.2 ± 1.0) × 10−5 |
[GLP-1RA], μM | ka1, M−1s−1 | kd1, s−1 | KD1, M | ka2, M−1s−1 | kd2, s−1 | KD2, M | |
Aβ40 | |||||||
Sema | 0.06–2 | (9.6 ± 2.4) × 103 | (3.2 ± 0.9) × 10−3 | (3.4 ± 0.5) × 10−7 | (3.90 ± 1.12) × 104 | (4.32 ± 0.12) × 10−2 | (1.2 ± 0.4) × 10−6 |
Lira | 1–8 | (1.44 ± 0.05) × 103 | (1.19 ± 0.13) × 10−3 | (9.5 ± 0.7) × 10−7 | (1.9 ± 0.3) × 103 | (1.70 ± 0.10) × 10−2 | (9.1 ± 1.6) × 10−6 |
Aβ42 | |||||||
Sema | 0.06–2 | (1.26 ± 0.11) × 104 | (4.1 ± 1.4) × 10−3 | (3.4 ± 1.4) × 10−7 | (1.34 ± 0.18) × 105 | (3.8 ± 0.7) × 10−2 | (3.0 ± 0.9) × 10−7 |
Lira | 1–8 | (2.24 ± 0.18) × 103 | (1.14 ± 0.10) × 10−3 | (5.2 ± 0.8) × 10−7 | (2.9 ± 0.04) × 103 | (1.64 ± 0.14) × 10−2 | (5.6 ± 0.3) × 10−6 |
GLP-1RA | [GLP-1RA], µM | Rh, nm | MWRh, kDa | MWRh/MWm |
---|---|---|---|---|
GLP-1(7-37) | 5–83 | >92 | >7 × 105 | >210 |
Lira | 105 | 3.08 ± 0.15 | 54.7 ± 7.8 | 15.6 ± 2.2 |
52 | 3.13 ± 0.05 | 57.1 ± 2.6 | 16.3 ± 0.7 | |
13 | 2.25 ± 0.12 | 22.7 ± 6.1 | 6.5 ± 1.7 | |
6 | 2.45 ± 0.16 | 28.8 ± 3.6 | 8.2 ± 1.0 | |
Exen | 234 | 2.20 ± 0.01 | 24.58 ± 0.02 | 5.88 ± 0.04 |
115 | 2.27 ± 0.16 | 26.7 ± 5.7 | 6.4 ± 1.4 | |
29 | 1.53 ± 0.06 | 8.8 ± 0.9 | 2.1 ± 0.2 | |
15 | 1.39 ± 0.07 | 6.7 ± 0.9 | 1.6 ± 0.2 | |
Sema | 47 | 1.22 ± 0.04 | 4.1 ± 0.4 | 1.2 ± 0.1 |
12 | 1.42 ± 0.15 | 6.2 ± 2.1 | 1.9 ± 0.6 |
Minimal KD for Aβ Binding According to BLI | Effect on Aβ40 Fibrillation (Figure 4 and Figure 5) | Effect on Aβ Cytotoxicity to SH-SY5Y Cells (Figure 7) | Ability to Cross the BBB | AD Animal Data | Clinical Data, AD | |
---|---|---|---|---|---|---|
Lira | 4.2 × 10−8 M | No effect | Protection | + [47] | Prevents memory loss, reduces Aβ amyloid deposits [47,48,49] | No effect [50] |
Sema | 1.1 × 10−5 M | Stimulation | Protection | − [74] | Positive effects on cognitive function, reduction of Aβ amyloid deposits [55] | Phase 3 clinical trials (NCT04777396 and NCT04777409) |
Exen | ~(0.4–1.5) × 10−5 M | Inhibition | Protection | + [73] | Positive effects on learning and memory ability, reduces Aβ deposition [38,39,40,41] | No effect [43] |
GLP-1(7-37) | ~(2.5–5.0) × 10−5 M | Inhibition | Increases Aβ40 cytotoxicity | + [24] | Positive effects on learning and memory [29] | No data |
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Litus, E.A.; Shevelyova, M.P.; Vologzhannikova, A.A.; Deryusheva, E.I.; Chaplygina, A.V.; Rastrygina, V.A.; Machulin, A.V.; Alikova, V.D.; Nazipova, A.A.; Permyakova, M.E.; et al. Interaction Between Glucagon-like Peptide 1 and Its Analogs with Amyloid-β Peptide Affects Its Fibrillation and Cytotoxicity. Int. J. Mol. Sci. 2025, 26, 4095. https://doi.org/10.3390/ijms26094095
Litus EA, Shevelyova MP, Vologzhannikova AA, Deryusheva EI, Chaplygina AV, Rastrygina VA, Machulin AV, Alikova VD, Nazipova AA, Permyakova ME, et al. Interaction Between Glucagon-like Peptide 1 and Its Analogs with Amyloid-β Peptide Affects Its Fibrillation and Cytotoxicity. International Journal of Molecular Sciences. 2025; 26(9):4095. https://doi.org/10.3390/ijms26094095
Chicago/Turabian StyleLitus, Ekaterina A., Marina P. Shevelyova, Alisa A. Vologzhannikova, Evgenia I. Deryusheva, Alina V. Chaplygina, Victoria A. Rastrygina, Andrey V. Machulin, Valeria D. Alikova, Aliya A. Nazipova, Maria E. Permyakova, and et al. 2025. "Interaction Between Glucagon-like Peptide 1 and Its Analogs with Amyloid-β Peptide Affects Its Fibrillation and Cytotoxicity" International Journal of Molecular Sciences 26, no. 9: 4095. https://doi.org/10.3390/ijms26094095
APA StyleLitus, E. A., Shevelyova, M. P., Vologzhannikova, A. A., Deryusheva, E. I., Chaplygina, A. V., Rastrygina, V. A., Machulin, A. V., Alikova, V. D., Nazipova, A. A., Permyakova, M. E., Dotsenko, V. V., Permyakov, S. E., & Nemashkalova, E. L. (2025). Interaction Between Glucagon-like Peptide 1 and Its Analogs with Amyloid-β Peptide Affects Its Fibrillation and Cytotoxicity. International Journal of Molecular Sciences, 26(9), 4095. https://doi.org/10.3390/ijms26094095