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

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• Tauopathies, including Alzheimer's disease, lack effective disease-modifying treatments.
• Pathological tau hyperphosphorylation correlates with disease progression and memory loss.
• 3-O-sulfated heparan sulfate is essential for tau hyperphosphorylation in zebrafish models.

Purpose of the Study:

• To investigate if surfen and its derivatives (oxalyl surfen, hemisurfen) can mitigate tau hyperphosphorylation and neuronal deficits.
• To assess the efficacy of heparan sulfate antagonists in a zebrafish model of tauopathies.

Main Methods:

• In vivo treatment of zebrafish embryos (Tg[HuC::hTauP301L; DsRed]) with surfen, oxalyl surfen, or hemisurfen.
• Quantification of tau phospho-epitopes using ELISA and Western blot.
• Immunohistochemical analysis of tau epitopes and neuronal morphology.
• Assessment of behavioral responses (touch-evoked escape response).

Main Results:

• Surfen and oxalyl surfen significantly reduced pThr181 tau epitope by 30% and 51%, respectively.
• Western blot confirmed decreased pThr181 and pSer396/pSer404 tau epitopes.
• Treatment rescued spinal motoneuron axon-branching defects and improved escape response.
• Hemisurfen, lacking heparan sulfate antagonist activity, showed no beneficial effects.

Conclusions:

• Surfen and oxalyl surfen show potential for mitigating neuronal defects in tauopathies.
• These findings suggest surfen's therapeutic potential for Alzheimer's disease and related disorders.
• Heparan sulfate antagonism represents a promising therapeutic strategy for tauopathies.