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Targeting p75NTR activity alleviates the neurotoxic effect of high glucose on iPSC-derived dopaminergic neurons.

Overview

Authors: Konstantina Chanoumidou1,2, Ioanna Zota1,2, Maria Anna Papadopoulou1,2, Chrystalla Konstantinou1,2, Alexandros Tsimpolis1,2, Electra Tsagliotis2, Maria Tziortziou3, Katerina Ntarntani1, Anne Grünewald3, Matthieu David Lavigne2, Achille Gravanis1,2, Ioannis Charalampopoulos1,2
ORCID iDs: Alexandros Tsimpolis, Anne Grünewald, Ioannis Charalampopoulos
  1. Department of Pharmacology, Medical School, University of Crete,71003 Heraklion, Greece
  2. Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas,71003 Heraklion, Greece
  3. Luxembourg Centre for Systems Biomedicine, University of Luxembourg,4362 Esch-sur-Alzette, Luxembourg
Institutions: University of Crete (Greece); Foundation for Research and Technology Hellas (Greece); University of Luxembourg (Luxembourg)
Journal: Stem cell research & therapy, volume 17, issue 1, article 161
Dates: received 22 July 2025; accepted 3 March 2026; published online 21 March 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1186/s13287-026-04965-y · PMID 41864949 · PMCID PMC13126899 · OpenAlex W7139970863
Open access: gold, a free copy (OpenAlex)
Status: data only (how the code is found and verified)
Categories: human (organism), other condition (population), Parkinson's (population), cellular / molecular (subfield)
Methods: Statistics
Keywords: iPSC, p75NTR, Neurotrophins, Dopaminergic neurons, Glucotoxicity, Neurodegeneration, Neuroinflammation
MeSH: Dopaminergic Neurons*, Glucose*, Induced Pluripotent Stem Cells*, Receptors, Nerve Growth Factor*, Astrocytes, DNA Damage, Humans, Hyperglycemia, Microglia, Nerve Tissue Proteins (* major topic)
Topic: Nerve injury and regeneration (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex
Funding: Bodossaki Postdoctoral Research Fellowship; EMBO Scientific Exchange Grant (STF_11143); National Research Fund (PRIDE21/16749720); Luxemburg National Research Fund (FNR) (FNR9631103); European Union—NextGenerationEU (TAEDR-0535850); EUROPEAN UNION HORIZON (No 101099145); Institute of Pharmaceutical Research and Technology (IFET S.A.)
Citations: not cited yet (Europe PMC); 92 references in the paper

Abstract

Background: Hyperglycemia, a hallmark of diabetes mellitus, is a metabolic condition that highly affects the nervous system. While evidence from epidemiological and animal studies links diabetes to dopaminergic dysfunction and an increased risk of Parkinson’s disease, the underlying mechanisms remain unclear. Here, we examined the effects of high glucose on human iPSC-derived dopaminergic neurons and glial cells to better understand the pathogenic alterations that lead to neurotoxicity. Previous implication of neurotrophins in the neurological manifestations of diabetes prompted us to focus on the role of p75NTR neurotrophin receptor (p75NTR) in dopaminergic neurodegeneration under hyperglycemic conditions.

Methods: iPSC-derived dopaminergic neurons, astrocytes and microglia were treated with high glucose (50mM, 100mM) for 48 h to simulate hyperglycemia. Cytotoxicity assays, RNA sequencing and DNA damage assessments were employed to investigate the pathological alterations induced by high glucose exposure in neurons. Pharmacological targeting of p75NTR activity allowed investigation of its involvement in glucose neurotoxicity. Glial-mediated neurotoxicity was evaluated using conditioned media and inflammatory marker analysis.

Results: High glucose treatment led to DNA damage, activation of JNK signaling and cell death in neurons. Importantly, we observed upregulation of p75NTR and its pro-apoptotic ligand pro-NGF, suggesting activation of the pro-NGF/p75NTR axis in high glucose-treated neurons. Inhibition of p75NTR activity rescued neuronal cell death, identifying p75NTR as a central mediator of glucose neurotoxicity. Furthermore, glucose overload sensitized neurons to 6-hydroxydopamine (6-OHDA), increasing their vulnerability to neurotoxic insults—an effect reversed by p75NTR blockade. Treatment with BNN27, a synthetic NGF mimetic, prevented neuronal loss through p75NTR and TrkA receptors, suggesting neurotrophin signaling as a potential therapeutic target for combating high glucose-induced neuronal damage. Finally, we demonstrated the contribution of glial cells to neurodegeneration since high glucose treatment of iPSC-derived astrocytes and microglia enhanced their inflammatory potential and triggered the release of neurotoxic factors, causing pro-apoptotic effects on neurons.

Conclusions: Our findings show that high glucose impairs human dopaminergic neuron survival through activation of the pro-NGF/p75NTR axis and indirect glia-mediated mechanisms. Targeting p75NTR signaling may offer neuroprotective benefits in diabetes-related neurodegeneration, particularly for patients at risk of Parkinson’s disease.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13287-026-04965-y.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Data availability

The datasets supporting the conclusions of this article are available in the GEO repository, GSE291145 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE291145. The following secure token has been created to allow review of record GSE291145 while it remains in private status: **gzqjakwgrlgvlcr.**.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 7 keywords, 10 MeSH terms, 7 funders, 90 references.

Cite

This paper

Chanoumidou, K., Zota, I., Papadopoulou, M. A., Konstantinou, C., Tsimpolis, A., Tsagliotis, E., Tziortziou, M., Ntarntani, K., Grünewald, A., Lavigne, M. D., Gravanis, A., & Charalampopoulos, I. (2026). Targeting p75NTR activity alleviates the neurotoxic effect of high glucose on iPSC-derived dopaminergic neurons. Stem cell research & therapy, 17(1), 161. https://doi.org/10.1186/s13287-026-04965-y

BibTeX

@article{chanoumidou2026targeting,
author = {Chanoumidou, Konstantina and Zota, Ioanna and Papadopoulou, Maria Anna and Konstantinou, Chrystalla and Tsimpolis, Alexandros and Tsagliotis, Electra and Tziortziou, Maria and Ntarntani, Katerina and Grünewald, Anne and Lavigne, Matthieu David and Gravanis, Achille and Charalampopoulos, Ioannis},
title = {{Targeting p75NTR activity alleviates the neurotoxic effect of high glucose on iPSC-derived dopaminergic neurons}},
journal = {Stem cell research \& therapy},
year = {2026},
month = mar,
volume = {17},
number = {1},
pages = {161},
publisher = {BMC},
issn = {1757-6512},
doi = {10.1186/s13287-026-04965-y},
url = {https://doi.org/10.1186/s13287-026-04965-y},
pmid = {41864949},
pmcid = {PMC13126899}
}

RIS

TY - JOUR
AU - Chanoumidou, Konstantina
AU - Zota, Ioanna
AU - Papadopoulou, Maria Anna
AU - Konstantinou, Chrystalla
AU - Tsimpolis, Alexandros
AU - Tsagliotis, Electra
AU - Tziortziou, Maria
AU - Ntarntani, Katerina
AU - Grünewald, Anne
AU - Lavigne, Matthieu David
AU - Gravanis, Achille
AU - Charalampopoulos, Ioannis
TI - Targeting p75NTR activity alleviates the neurotoxic effect of high glucose on iPSC-derived dopaminergic neurons
T2 - Stem cell research & therapy
J2 - Stem Cell Res Ther
PY - 2026
DA - 2026/03/21
VL - 17
IS - 1
SP - 161
SN - 1757-6512
PB - BMC
DO - 10.1186/s13287-026-04965-y
UR - https://doi.org/10.1186/s13287-026-04965-y
LA - en
ER -

CSL-JSON

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