New BDNF and NT-3 Cyclic Mimetics Concur with Copper to Activate Trophic Signaling Pathways as Potential Molecular Entities to Protect Old Brains from Neurodegeneration
Abstract
:1. Introduction
2. Materials and Methods
2.1. Design and Synthesis
2.2. NMR Measurements
2.3. Potentiometric Titrations
2.4. Ultraviolet-Visible (UV-Vis) Measurements
2.5. Circular Dichroism (CD) Measurements
2.6. Inductively Coupled Plasma—Optical Emission Spectroscopy
2.7. Cell Culture Reagents and Antibodies
2.8. Cell Culture and Treatment Conditions
2.9. Neuronal Differentiation of SH-SY5Y by Neurite Outgrowth Analysis
2.10. Determination of Ctr1 Translocation by Immunofluorescence Assay
2.11. Protein Lysate Preparation and Immunoblotting
2.12. Sandwich ELISA Assay
2.13. Statistical Analysis
3. Results
3.1. cBDNF(1-12) and cNT3(1−13) Are Cyclic Peptides Which Show Different Secondary Structures
3.2. cBDNF(1-12) and cNT3(1-13) Show Different Speciation and Binding Affinity for the Copper(II) Ion
3.3. Conditional Dissociation Constant Values (cKd) Allow for a Comparison of Different Affinity of the Two Peptides
3.4. Copper(II) Ion Is Present at Sub-Micromolar Concentration in Culture Media Supplemented with Serum
3.5. cNT3(1-13) and cBDNF(1-12) Mimic the Neuronal Differentiation Capability of NTs in SH-SY5Y Neuroblastoma Cells
3.6. cNT-3(1-13) and cBDNF(1-12) Are Ionophore Peptides and Induce a Decrease of Ctr1 Localization on Cell Membrane
3.7. cNT3(1-13) and cBDNF(1-12) Increase TrkA and TrkB as Well as VEGFR1 and VEGFR2 Receptors Expression
3.8. cNT3(1-13) and cBDNF(1-12) Promote Trk Signaling Cascade by CREB Phosphorylation in a Copper Dependent Manner
3.9. cNT3(1-13)/ and cBDNF(1-12)/Trk Pathway Stimulate Expression of Trophic Factors and the Release of VEGF
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Protein | Company and Code | Dilution and Application |
---|---|---|
phospho-Trk | SantaCruz (Santa Cruz, CA, USA), sc-8058 | 1:500 for western blotting assay |
phospho-CREB | SantaCruz (Santa Cruz, CA, USA), sc-8058 | 1:500 for western blotting assay |
VEGFR1 | SantaCruz (Santa Cruz, CA, USA), sc-271789 | 1:500 for western blotting assay |
VEGFR2 | SantaCruz (Santa Cruz, CA, USA), sc-6251 | 1:500 for western blotting assay |
TrkA | Cell Signaling (Danvers, MA, USA), #2505 | 1:800 for western blotting assay |
TrkB | Abcam Waltham, MA, USA), ab33655 | 1:1000 for western blotting assay |
anti-Ctr1 | Abcam Waltham, MA, USA), ab129067 | 1:3000 for western blotting assay 2.5 µg/mL for immunofluorescence assay |
anti-VEGF | SantaCruz, sc-72693 | 1:500 for western blotting assay 1:50 for ELISA |
anti-BDNF | SantaCruz, sc-65513 | 1:500 for western blotting assay |
anti-GAPDH | Abcam (Waltham, MA, USA), ab8245 | 1:3000 for western blotting assay |
anti-Actin | Sigma Aldrich (St. Louis, MO, USA), A3853 | 1:2000 for western blotting assay |
Species [LqHr] c | cBDNF(1-12) | cNT3(1-13) | ||
---|---|---|---|---|
log β d | pK | log β d | pK | |
11 | 6.60 (3) | 6.60 | - | - |
12 | 11.31 (4) | 4.71 | 20.01 (1) | 10.00 × 2 |
13 | 15.07 (4) | 3.76 | 29.11 (2) | 9.10 |
14 | - | - | 35.78 (3) | 6.67 |
15 | - | - | 41.81 (3) | 6.03 |
16 | - | - | 46.36 (4) | 4.55 |
17 | - | - | 50.31 (3) | 3.95 |
Species [CupLqHr] c | cBDNF(1-12) | cNT3(1-13) | ||
---|---|---|---|---|
log β d | pK | log β d | pK | |
114 | - | - | 40.58 (1) | - |
113 | - | - | 35.77 (1) | 4.81 |
112 | - | - | 28.73 (3) | 7.04 |
111 | - | - | 21.82 (1) | 6.91 |
110 | 4.77 (5) | - | 13.90 (2) | 7.92 |
11-1 | - | 4.57 (3) | 9.34 | |
11-2 | −7.30 (4) | 6.03 × 2 | −5.68 (2) | 10.24 |
11-3 | −15.81 (5) | 8.51 | −15.88 (2) | 10.20 |
L | Species [CupLqHr] | UV-Vis λ (nm) (ε, M−1 cm−1) | CD λ (nm) (Δε, M−1 cm−1) |
---|---|---|---|
CuL | 686 (75) | 254 (+1.11); 337 (+0.13) | |
cBDNF(1-12) | CuLH−2 | 590 (99) | 254 (+3.17); 340 (+1.33); 578 (−0.78) |
CuLH−3 | 546 (117) | 270 (+3.54), 308 (+1.51), 479 (+0.38), 555 (−1.31) | |
CuLH3 | 688 (55) | 260 (+1.31) | |
CuLH | 596 (65) | 260 (+2.01), 316 (+0.15), 356 (−0.20), 475 (−0.19), 553 (+0.10) | |
cNT3(1-13) | CuL | 512 (113) | 260 (+4.22), 319 (+0.90), 358 (−0.15), 488 (−1.07), 612 (+0.81) |
CuLH−1 | 512 (120) | 260 (+4.50), 319 (+0.95), 358 (−0.12), 490 (−1.13), 614 (+0.86) | |
CuLH−3 | 515 (95) | 260 (+4.60), 319 (+0.92), 358 (−0.12), 496 (−0.94), 617 (+0.54) |
Peptide | cKd (M−1) |
---|---|
cNT3(1-13) | 1.99 × 10−8 |
cBDNF(1-12) | 3.42 × 10−8 |
cNGF(1-14) | 1.49 × 10−7 |
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Magrì, A.; Tomasello, B.; Naletova, I.; Tabbì, G.; Cairns, W.R.L.; Greco, V.; Sciuto, S.; La Mendola, D.; Rizzarelli, E. New BDNF and NT-3 Cyclic Mimetics Concur with Copper to Activate Trophic Signaling Pathways as Potential Molecular Entities to Protect Old Brains from Neurodegeneration. Biomolecules 2024, 14, 1104. https://doi.org/10.3390/biom14091104
Magrì A, Tomasello B, Naletova I, Tabbì G, Cairns WRL, Greco V, Sciuto S, La Mendola D, Rizzarelli E. New BDNF and NT-3 Cyclic Mimetics Concur with Copper to Activate Trophic Signaling Pathways as Potential Molecular Entities to Protect Old Brains from Neurodegeneration. Biomolecules. 2024; 14(9):1104. https://doi.org/10.3390/biom14091104
Chicago/Turabian StyleMagrì, Antonio, Barbara Tomasello, Irina Naletova, Giovanni Tabbì, Warren R. L. Cairns, Valentina Greco, Sebastiano Sciuto, Diego La Mendola, and Enrico Rizzarelli. 2024. "New BDNF and NT-3 Cyclic Mimetics Concur with Copper to Activate Trophic Signaling Pathways as Potential Molecular Entities to Protect Old Brains from Neurodegeneration" Biomolecules 14, no. 9: 1104. https://doi.org/10.3390/biom14091104