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Surfen and oxalyl surfen decrease tau hyperphosphorylation and mitigate neuron deficits in vivo in a zebrafish model of tauopathy
BACKGROUND: Tauopathies comprise a family of neurodegenerative disorders including Alzheimer’s disease for which there is an urgent and unmet need for disease-modifying treatments. Tauopathies are characterized by pathological tau hyperphosphorylation, which has been shown to correlate tightly with...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855975/ https://www.ncbi.nlm.nih.gov/pubmed/29568517 http://dx.doi.org/10.1186/s40035-018-0111-2 |
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author | Alavi Naini, Seyedeh Maryam Yanicostas, Constantin Hassan-Abdi, Rahma Blondeel, Sébastien Bennis, Mohamed Weiss, Ryan J. Tor, Yitzhak Esko, Jeffrey D. Soussi-Yanicostas, Nadia |
author_facet | Alavi Naini, Seyedeh Maryam Yanicostas, Constantin Hassan-Abdi, Rahma Blondeel, Sébastien Bennis, Mohamed Weiss, Ryan J. Tor, Yitzhak Esko, Jeffrey D. Soussi-Yanicostas, Nadia |
author_sort | Alavi Naini, Seyedeh Maryam |
collection | PubMed |
description | BACKGROUND: Tauopathies comprise a family of neurodegenerative disorders including Alzheimer’s disease for which there is an urgent and unmet need for disease-modifying treatments. Tauopathies are characterized by pathological tau hyperphosphorylation, which has been shown to correlate tightly with disease progression and memory loss in patients suffering from Alzheimer’s disease. We recently demonstrated an essential requirement for 3-O-sulfated heparan sulfate in pathological tau hyperphosphorylation in zebrafish, a prominent model organism for human drug discovery. Here, we investigated whether in vivo treatment with surfen or its derivatives oxalyl surfen and hemisurfen, small molecules with heparan sulfate antagonist properties, could mitigate tau hyperphosphorylation and neuronal deficits in a zebrafish model of tauopathies. RESULTS: In vivo treatment of Tg[HuC::hTau(P301L); DsRed] embryos for 2 days with surfen or oxalyl surfen significantly reduced the accumulation of the pThr181 tau phospho-epitope measured by ELISA by 30% and 51%, respectively. Western blot analysis also showed a significant decrease of pThr181 and pSer396/pSer404 in embryos treated with surfen or oxalyl surfen. Immunohistochemical analysis further confirmed that treatment with surfen or oxalyl surfen significantly decreased the AT8 tau epitope in spinal motoneurons. In addition, in vivo treatment of Tg[HuC::hTau(P301L); DsRed] embryos with surfen or oxalyl surfen significantly rescued spinal motoneuron axon-branching defects and, as a likely consequence, the impaired stereotypical touch-evoked escape response. Importantly, treatment with hemisurfen, a surfen derivative devoid of heparan sulfate antagonist activity, does not affect tau hyperphosphorylation, nor neuronal or behavioural deficits in Tg[HuC::hTau(P301L); DsRed] embryos. CONCLUSION: Our findings demonstrate for the first time that surfen, a well-tolerated molecule in clinical settings, and its derivative, oxalyl surfen, could mitigate or delay neuronal defects in tauopathies, including Alzheimer’s disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40035-018-0111-2) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5855975 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-58559752018-03-22 Surfen and oxalyl surfen decrease tau hyperphosphorylation and mitigate neuron deficits in vivo in a zebrafish model of tauopathy Alavi Naini, Seyedeh Maryam Yanicostas, Constantin Hassan-Abdi, Rahma Blondeel, Sébastien Bennis, Mohamed Weiss, Ryan J. Tor, Yitzhak Esko, Jeffrey D. Soussi-Yanicostas, Nadia Transl Neurodegener Short Report BACKGROUND: Tauopathies comprise a family of neurodegenerative disorders including Alzheimer’s disease for which there is an urgent and unmet need for disease-modifying treatments. Tauopathies are characterized by pathological tau hyperphosphorylation, which has been shown to correlate tightly with disease progression and memory loss in patients suffering from Alzheimer’s disease. We recently demonstrated an essential requirement for 3-O-sulfated heparan sulfate in pathological tau hyperphosphorylation in zebrafish, a prominent model organism for human drug discovery. Here, we investigated whether in vivo treatment with surfen or its derivatives oxalyl surfen and hemisurfen, small molecules with heparan sulfate antagonist properties, could mitigate tau hyperphosphorylation and neuronal deficits in a zebrafish model of tauopathies. RESULTS: In vivo treatment of Tg[HuC::hTau(P301L); DsRed] embryos for 2 days with surfen or oxalyl surfen significantly reduced the accumulation of the pThr181 tau phospho-epitope measured by ELISA by 30% and 51%, respectively. Western blot analysis also showed a significant decrease of pThr181 and pSer396/pSer404 in embryos treated with surfen or oxalyl surfen. Immunohistochemical analysis further confirmed that treatment with surfen or oxalyl surfen significantly decreased the AT8 tau epitope in spinal motoneurons. In addition, in vivo treatment of Tg[HuC::hTau(P301L); DsRed] embryos with surfen or oxalyl surfen significantly rescued spinal motoneuron axon-branching defects and, as a likely consequence, the impaired stereotypical touch-evoked escape response. Importantly, treatment with hemisurfen, a surfen derivative devoid of heparan sulfate antagonist activity, does not affect tau hyperphosphorylation, nor neuronal or behavioural deficits in Tg[HuC::hTau(P301L); DsRed] embryos. CONCLUSION: Our findings demonstrate for the first time that surfen, a well-tolerated molecule in clinical settings, and its derivative, oxalyl surfen, could mitigate or delay neuronal defects in tauopathies, including Alzheimer’s disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40035-018-0111-2) contains supplementary material, which is available to authorized users. BioMed Central 2018-03-16 /pmc/articles/PMC5855975/ /pubmed/29568517 http://dx.doi.org/10.1186/s40035-018-0111-2 Text en © The Author(s). 2018, corrected publication [2020] Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Short Report Alavi Naini, Seyedeh Maryam Yanicostas, Constantin Hassan-Abdi, Rahma Blondeel, Sébastien Bennis, Mohamed Weiss, Ryan J. Tor, Yitzhak Esko, Jeffrey D. Soussi-Yanicostas, Nadia Surfen and oxalyl surfen decrease tau hyperphosphorylation and mitigate neuron deficits in vivo in a zebrafish model of tauopathy |
title | Surfen and oxalyl surfen decrease tau hyperphosphorylation and mitigate neuron deficits in vivo in a zebrafish model of tauopathy |
title_full | Surfen and oxalyl surfen decrease tau hyperphosphorylation and mitigate neuron deficits in vivo in a zebrafish model of tauopathy |
title_fullStr | Surfen and oxalyl surfen decrease tau hyperphosphorylation and mitigate neuron deficits in vivo in a zebrafish model of tauopathy |
title_full_unstemmed | Surfen and oxalyl surfen decrease tau hyperphosphorylation and mitigate neuron deficits in vivo in a zebrafish model of tauopathy |
title_short | Surfen and oxalyl surfen decrease tau hyperphosphorylation and mitigate neuron deficits in vivo in a zebrafish model of tauopathy |
title_sort | surfen and oxalyl surfen decrease tau hyperphosphorylation and mitigate neuron deficits in vivo in a zebrafish model of tauopathy |
topic | Short Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855975/ https://www.ncbi.nlm.nih.gov/pubmed/29568517 http://dx.doi.org/10.1186/s40035-018-0111-2 |
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