Neurotrophic Activity and Its Modulation by Zinc Ion of a Dimeric Peptide Mimicking the Brain-Derived Neurotrophic Factor N-Terminal Region
Lara Russo, Chiara Giacomelli, Mariagrazia Fortino, Tiziano Marzo, Gianmarco Ferri, Mariantonietta Calvello et al. · 2022 · 16 citationsRead the paper
Brain-derived neurotrophic factor (BDNF) is a neurotrophin (NT) essential for neuronal development and synaptic plasticity. Dysregulation of BDNF signaling is implicated in different neurological disorders. The direct NT administration as therapeutics has revealed to be challenging. This has prompted the design of peptides mimicking different regions of the BDNF structure. Although loops 2 and 4 have been thoroughly investigated, less is known regarding the BDNF N-terminal region, which is involved in the selective recognition of the TrkB receptor. Herein, a dimeric form of the linear peptide encompassing the 1-12 residues of the BDNF N-terminal (d-bdnf) was synthesized. It demonstrated to act as an agonist promoting specific phosphorylation of TrkB and downstream ERK and AKT effectors. The ability to promote TrkB dimerization was investigated by advanced fluorescence microscopy and molecular dynamics (MD) simulations, finding activation modes shared with BDNF. Furthermore, d-bdnf was able to sustain neurite outgrowth and increase the expression of differentiation (NEFM, LAMC1) and polarization markers (MAP2, MAPT) demonstrating its neurotrophic activity. As TrkB activity is affected by zinc ions in the synaptic cleft, we first verified the ability of d-bdnf to coordinate zinc and then the effect of such complexation on its activity. The d-bdnf neurotrophic activity was reduced by zinc complexation, demonstrating the role of the latter in tuning the activity of the new peptido-mimetic. Taken together our data uncover the neurotrophic properties of a novel BDNF mimetic peptide and pave the way for future studies to understand the pharmacological basis of d-bdnf action and develop novel BDNF-based therapeutic strategies.
What the full text shows
Shown in the lab- The dimeric peptide d-bdnf acts as a specific TrkB agonist, promoting phosphorylation of TrkB and downstream ERK and AKT effectors. — EC50 = 13.63 ± 3.87 μM (for ERK phosphorylation) (SH-SY5Y cells expressing recombinant GFP-fusion human TrkB)
- d-bdnf sustains neurite outgrowth and increases expression of differentiation (LAMC1, NEFM) and polarization (MAP2, MAPT) markers. — Similar effect to nM concentrations of BDNF at 1 and 5 μM d-bdnf (Differentiated SH-SY5Y cells)
- d-bdnf increases the neuronal cell fraction of differentiated human neural progenitor cells. — Significant increase vs. untreated cells (RenVM cell line)
- Zinc complexation reduces the neurotrophic activity of the d-bdnf peptide. — Reduced activity with equimolar amounts of coordinated zinc (d-bdnf peptide in the presence of Zn2+ ions)
- d-bdnf coordinates a single zinc ion, likely at the terminal histidine residues. — 1:1 metal to ligand stoichiometry (HR-ESI-MS and CD spectra analysis)
- Setup
- SH-SY5Y and RenVM human cell lines; recombinant GFP-fusion human TrkB; dimeric (d-bdnf), monomeric (m-bdnf), and scrambled (s-bdnf) peptides.
- How
- The researchers synthesized a dimeric peptide (d-bdnf) mimicking the BDNF N-terminal (residues 1-12) and evaluated its activity via Western blot, fluorescence microscopy, and RT-PCR in SH-SY5Y and RenVM cells. They used HR-ESI-MS, CD spectra, and molecular dynamics simulations to study zinc coordination and TrkB receptor dimerization.
- Limitations
- d-bdnf is significantly less potent than full-length BDNF (μM vs nM range). · d-bdnf does not significantly increase GAP43 expression, likely due to lack of p75 NTR activation. · Higher concentrations (10 μM) of d-bdnf are less effective in long-term neurite outgrowth assays compared to short-term phosphorylation assays.
Summarized by Gemma 4 from the open-access full text · 8 Oct 2026. Read it