Surfen and oxalyl surfen decrease tau hyperphosphorylation and mitigate neuron deficits in vivo in a zebrafish model of tauopathy

查看全文 作　　者：Seyedeh Maryam Alavi [1,2]Naini;Constantin [1]Yanicostas;Rahma Hassan-[1]Abdi;Sébastien [1]Blondeel;Mohamed [3]Bennis;Ryan [4]J.Weiss;Yitzhak [4]Tor;Jeffrey [5]D.Esko;Nadia Soussi-[1]Yanicostas

机构地区：[1]PROTECT,Inserm,UniversitéParis Diderot,Sorbonne Paris Cité,Paris,France;[2]Institut de Biologie Paris Seine-Laboratoire Neuroscience Paris Seine,Inserm UMRS 1130,CNRS UMR 8246,UPMC UM 118,UniversitéPierre et Marie Curie,Paris,France;[3]Cadi Ayyad University,Marrakesh,Morocco;[4]Department of Chemistry and Biochemistry,University of California,San Diego,La Jolla,CA,USA;[5]Department of Cellular and Molecular Medicine,University of California,San Diego,La Jolla,CA,USA

出　　处：《Translational Neurodegeneration》索引2018年第7卷第1期,共9页

基　　金：This work was supported by Institut National de la Santéet la Recherche Médicale(INSE RM),the French National Research Agency(ANR-16-CE18–0010);Fondation NRJ(Institut de France)to NSY and grants CA46462 and CA112278 from the National Institute of Health to JDE and YT. 摘　　要：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. 关键词：TAUOPATHY ZEBRAFISH Alzheimer’s disease TAU protein TAU HYPERPHOSPHORYLATION Surfen Oxalyl surfen Heparan sulfate

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Surfen and oxalyl surfen decrease tau hyperphosphorylation and mitigate neuron deficits in vivo in a zebrafish model of tauopathy

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