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Article Dans Une Revue Pharmacological Research Année : 2020

Neuroprotective brain-derived neurotrophic factor signaling in the TAU-P301L tauopathy zebrafish model

Résumé

Brain-derived neurotrophic factor (BDNF) dysregulations contribute to the neurotoxicity in neurodegenerative pathologies and could be efficiently targeted by therapies. In Alzheimer's disease (AD), although the relationship between BDNF and amyloid load has been extensively studied, how Tau pathology affects BDNF signaling remains unclear. Using the TAU-P301L transgenic zebrafish line, we investigated how early Tau-induced neuro-toxicity modifies BDNF signaling. Alterations in BDNF expression levels were observed as early as 48 h post fertilization in TAU-P301L zebrafish embryos while TrkB receptor expression was not affected. Decreasing BDNF expression, using a knockdown strategy in wild-type embryos to mimic Tau-associated decrease, did not modify TrkB expression but promoted neurotoxicity as demonstrated by axonal outgrowth shortening and neuronal cell death. Moreover, the TrkB antagonist ANA-12 reduced the length of axonal projections. Rescue experiments with exogenous BDNF partially corrected neuronal alterations in TAU-P301L by counteracting primary axonal growth impairment but without effect on apoptosis. Importantly, the axonal rescue was proved functionally effective in a behavioral test, at a similar level as obtained with the GSK3β inhibitor LiCl, known to decrease TAU phos-phorylation. Finally, treatment with a TrkB agonist, 7,8-dihydroxyflavone, led to comparable results and allowed full rescue of locomotor response. We provided here strong evidence that Tau neurotoxicity provoked alterations in BDNF system and that BDNF pathway might represent an efficient therapeutic target.

Domaines

Neurobiologie
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Dates et versions

hal-02965481 , version 1 (13-10-2020)

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Clément Barbereau, Alaa Yehya, Michelle Silhol, Nicolas Cubedo, Jean-Michel Verdier, et al.. Neuroprotective brain-derived neurotrophic factor signaling in the TAU-P301L tauopathy zebrafish model. Pharmacological Research, 2020, 158, pp.104865. ⟨10.1016/j.phrs.2020.104865⟩. ⟨hal-02965481⟩
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