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

Abstract

BackgroundTauopathies 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.ResultsIn vivo treatment of Tg[HuC::hTauP301L; 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::hTauP301L; 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::hTauP301L; DsRed] embryos.ConclusionOur 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 materialThe online version of this article (10.1186/s40035-018-0111-2) contains supplementary material, which is available to authorized users.

Neurons Expressing Pathological Tau Protein Trigger Dramatic Changes in Microglial Morphology and Dynamics

“…For whole mount immunostaining, 5 dpf wild-type embryos with or without microglia, were fixed in 4% formaldehyde in PBS for 1 h 30 min at room temperature, washed three times in PBS (10 min each) and permeabilized in cold acetone (−20°C) for 20 min. After several washes, embryos were incubated in collagenase solution for 1 h. Immunohistochemistry was performed as described previously (Naini et al, 2018) using rabbit anti-zebrafish L-plastin polyclonal antibody (gift of Dr. Michael Redd, University College London, United Kingdom), followed by Alexa-coupled secondary anti-rabbit antibody (Molecular Probes) at 1:500 dilution. After washing, the fluorescence was analyzed using a Leica TCS SP8 confocal scanning system (Leica Microsystems).…”

A Fast, Simple, and Affordable Technique to Measure Oxygen Consumption in Living Zebrafish Embryos

“… 3 , 4 As previously reported, we found that 1% DMSO concentration had no effect on larval development. 5 …”

Heparan Sulfate as a Therapeutic Target in Tauopathies: Insights From Zebrafish

“…Surfen, a non-specific heparan sulfate antagonist interferes with numerous biological processes, showing potential as a therapeutic agent. The properties of surfen ranges from anti-inflammatory (Warford et al, 2018) and immuomodulatory (Warford et al, 2014) to suppression of stem cell differentiation (Huang et al, 2018), inhibition of HIV type 1 infection (Roan et al, 2010) and rescue of tauopathy in a zebrafish model (Alavi Naini et al, 2018). However, non-specificity limits the beneficial effects of surfen.…”

“…An additional approach consists of treatment with heparan sulfate antagonist molecules. In a recent proof of concept study a rescue of neuronal abnormalities upon treatment with surfen and oxalyl surfen was observed in the Tg[HuC::hTau P301L /DsRed] zebrafish model (Alavi Naini et al, 2018). Figure 1 summarizes the two approaches in Tg[HuC::hTau P301L /DsRed] zebrafish.…”

“…Combination of genetic (A) (morpholino gene-KO) (Sepulveda-Diaz et al, 2015) and pharmacological (B) (small molecule) (Alavi Naini et al, 2018) approaches in the zebrafish Tg[HuC::hTau P301L ; DsRed] tauopathy model identified 3- OS -sulfated HS as a therapeutic target for tauopathies and the small molecules surfen and oxalyl surfen as novel therapeutic candidates.…”