OSCR

Hexaraphane as a potential therapeutic strategy for tauopathies.

Overview

Authors: Ángel Juan García-Yagüe1,2,3,4, Daniel Carnicero-Senabre1,2,3,4, Ángel Núñez5, Raffaela Cipriani6, Estibaliz Capetillo-Zarate6,7,8, Maribel Escoll1,2,3,4, Isao Okunishi9, Ana I Rojo1,2,3,4, Antonio Cuadrado1,2,3,4
ORCID iDs: Ángel Juan García-Yagüe
  1. Department of Biochemistry, School of Medicine, Autonomous University of Madrid (UAM), Madrid, Spain
  2. Instituto de Investigaciones Biomédicas “Sols-Morreale” (CSIC-UAM), Madrid, Spain
  3. Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain
  4. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
  5. Department of Anatomy, Histology and Neuroscience, Autonomous University of Madrid, Madrid, Spain
  6. Platform for Biomarkers, Achucarro Basque Center for Neuroscience, Leioa, 48940, Spain
  7. IKERBASQUE, Basque Foundation for Science, Bilbao, 48009, Spain
  8. Department of Neurosciences, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, 01008, Spain
  9. Kinjirushi Co., Ltd, 2-61 Yahata-hontori, Nakagawa-ku, Nagoya, Aichi, 454-8526, Japan
Institutions: Biomedical Research Networking Center on Neurodegenerative Diseases (Spain); Instituto de Investigaciones Biomédicas Sols-Morreale (Spain); Centro de Investigación Biomédica en Red (Spain); Universidad Autónoma de Madrid (Spain); Consejo Superior de Investigaciones Científicas (Spain); Achucarro Basque Center for Neuroscience (Spain); Ikerbasque (Spain); University of the Basque Country (Spain)
Journal: Redox biology, volume 92, article 104107
Dates: received 14 January 2026; accepted 1 March 2026; published online 2 March 2026; in print May 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1016/j.redox.2026.104107 · PMID 41785736 · PMCID PMC12969043 · OpenAlex W7133224995
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: mouse (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Statistics, Evoked potentials
Keywords: NRF2, Hexaraphane, Tauopathies, PP2A, Neurodegeneration, Alzheimer's disease
MeSH: Brain*, Isothiocyanates*, tau Proteins*, Tauopathies*, Animals, Glycogen Synthase Kinase 3 beta, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Phosphorylation, Primary Cell Culture, Protein Phosphatase 2, Wasabia (* major topic)
Topic: Alzheimer's disease research and treatments (Physiology, Medicine), according to OpenAlex
Funding: Berrikuntza + Ikerketa + Osasuna Eusko Fundazioa (BIO22/ALZ/014); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas; State Agency of Research (PID2021-122650OB-I00, PDC2022-133765-I00, PID2022-141786OB-I00, CPP2021-008389, PDC2021-121421-I00, PID2022-140236OB-I00); Eusko Jaurlaritza; Basque Foundation for Science (IT1551- 22); Community of Madrid (P2022_BMD-7230); Instituto de Salud Carlos III (CB06/05/0010)
Citations: not cited yet (Europe PMC); 72 references in the paper

Abstract

Alzheimer's disease (AD) is characterized by pathological hyperphosphorylation of TAU protein, leading to neurofibrillary tangle formation, synaptic dysfunction, neuroinflammation, and neuronal loss. Hexaraphane (6-(methylsulfinyl) hexyl isothiocyanate; HXN), a bioactive compound derived from Wasabia japonica, exhibits neuroprotective and anti-inflammatory properties, yet its potential role in tauopathies remains unknown. Here, we investigated whether HXN modulates pathological TAU phosphorylation and explored the underlying mechanisms in vitro and in vivo. Using primary neurons from APP/TAU transgenic mice with either NRF2 wild-type or knockout backgrounds, combined with complementary genetic and pharmacological approaches, we found that HXN markedly reduced pathological phospho-TAU epitopes (AT8 and PHF1). Notably, this effect occurred independently of NRF2 signaling. Mechanistically, HXN did not suppress GSK-3β activity or alter upstream PI3K/AKT or MAPK pathways. Instead, pharmacological inhibition experiments and phosphatase assays demonstrated that HXN promotes PP2A-dependent TAU dephosphorylation, identifying phosphatase activation as a central mechanism of action. Chronic oral administration of HXN in APP/TAU mice led to significant reductions in brain phospho-TAU levels across multiple regions and decreased blood circulating TAU-pThr217 concentrations. These molecular changes were accompanied by attenuation of neuroinflammatory markers, preservation of neuronal integrity, restoration of synaptic plasticity, and improvements in cognitive and motor performance. Collectively, our findings identify HXN as a potent modulator of pathological TAU phosphorylation. These results support the development of HXN as a promising disease-modifying therapeutic strategy for AD and other TAU-driven neurodegenerative disorders.

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

Code

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Data

Datasets cited

Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Data will be made available on request.

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

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 9 authors, 6 keywords, 14 MeSH terms, 7 funders, 72 references.

Cite

This paper

García-Yagüe, Á. J., Carnicero-Senabre, D., Núñez, Á., Cipriani, R., Capetillo-Zarate, E., Escoll, M., Okunishi, I., Rojo, A. I., & Cuadrado, A. (2026). Hexaraphane as a potential therapeutic strategy for tauopathies. Redox biology, 92, 104107. https://doi.org/10.1016/j.redox.2026.104107

BibTeX

@article{garciayague2026hexaraphane,
author = {García-Yagüe, Ángel Juan and Carnicero-Senabre, Daniel and Núñez, Ángel and Cipriani, Raffaela and Capetillo-Zarate, Estibaliz and Escoll, Maribel and Okunishi, Isao and Rojo, Ana I and Cuadrado, Antonio},
title = {{Hexaraphane as a potential therapeutic strategy for tauopathies}},
journal = {Redox biology},
year = {2026},
month = mar,
volume = {92},
pages = {104107},
publisher = {Elsevier},
issn = {2213-2317},
doi = {10.1016/j.redox.2026.104107},
url = {https://doi.org/10.1016/j.redox.2026.104107},
pmid = {41785736},
pmcid = {PMC12969043}
}

RIS

TY - JOUR
AU - García-Yagüe, Ángel Juan
AU - Carnicero-Senabre, Daniel
AU - Núñez, Ángel
AU - Cipriani, Raffaela
AU - Capetillo-Zarate, Estibaliz
AU - Escoll, Maribel
AU - Okunishi, Isao
AU - Rojo, Ana I
AU - Cuadrado, Antonio
TI - Hexaraphane as a potential therapeutic strategy for tauopathies
T2 - Redox biology
J2 - Redox Biol
PY - 2026
DA - 2026/03/02
VL - 92
SP - 104107
SN - 2213-2317
PB - Elsevier
DO - 10.1016/j.redox.2026.104107
UR - https://doi.org/10.1016/j.redox.2026.104107
LA - en
ER -

CSL-JSON

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