Neuroprotective Brain-Derived Neurotrophic Factor signaling in the TAU-P301L tauopathy zebrafish model
- Barbereau, C., Yehya, A., Silhol, M., Cubedo, N., Verdier, J.M., Maurice, T., Rossel, M.
- Pharmacological research 158: 104865 (Journal)
- Registered Authors
- Cubedo, Nicolas, Rossel, Mireille
- BDNF signaling, TAU-P301L mutation, Tauopathies, TrkB, Zebrafish
- MeSH Terms
- Axons/drug effects
- Behavior, Animal/drug effects
- Brain-Derived Neurotrophic Factor/agonists
- Brain-Derived Neurotrophic Factor/biosynthesis
- Brain-Derived Neurotrophic Factor/genetics*
- Brain-Derived Neurotrophic Factor/pharmacology
- Cell Death
- Neuroprotective Agents*
- Primary Cell Culture
- Receptor, trkB/biosynthesis
- Recombinant Proteins/pharmacology
- Tauopathies/drug therapy*
- 32417505 Full text @ Pharmacol. Res.
Barbereau, C., Yehya, A., Silhol, M., Cubedo, N., Verdier, J.M., Maurice, T., Rossel, M. (2020) Neuroprotective Brain-Derived Neurotrophic Factor signaling in the TAU-P301L tauopathy zebrafish model. Pharmacological research. 158:104865.
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-P301 L transgenic zebrafish line, we investigated how early Tau-induced neurotoxicity modifies BDNF signaling. Alterations in BDNF expression levels were observed as early as 48 h post fertilization in TAU-P301 L 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-P301 L 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 phosphorylation. 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.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes