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

Abstract

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 neurotoxicity modifies BDNF signaling. Alterations in BDNF expression levels were observed as early as 48 h post fertilization in TAU-P301L zebrafish embryos while TrkB expression was not modified. Decreasing BDNF expression, using a knockdown strategy in wild-type embryos to mimic Tau-associated decrease, did not modify receptor expression but promoted neurotoxicity as seen 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 GSK3b inhibitor LiCl, used as positive control. Finally, treatment with a TrkB agonist, 7,8-dihydroxyflavone, gave comparable results and allowed full rescue of locomotor response. We provided here strong evidences that Tau neurotoxicity provoked alterations in BDNF system and that BDNF pathway might represent an efficient therapeutic target.

Advances of Zebrafish in Neurodegenerative Disease: From Models to Drug Discovery

“…Zebrafish larvae can be placed in a 96-well plate with one larva per well for highthroughput drug screening. A chamber with a digital control can change the light and dark periods in cycles and monitor the movement of zebrafish larvae (Pan et al, 2019;Barbereau et al, 2020). Another method in larger adult zebrafish is to assess the time spend in the light compartment or the latency to enter the dark compartment.…”

“…The GSK-3β inhibitor, lithium chloride can reverse cognitive deficits and tau hyperphosphorylation in an in vivo AD model, which was established by injecting Aβ42 into the hindbrain ventricle of zebrafish embryos (Nery et al, 2014). Lithium chloride is also used as a positive control to protect zebrafish locomotors or dephosphorylation for tauopathy in the Tau-P301L-Tg zebrafish model Barbereau et al, 2020). Another form of lithium, lithium carbonate (Li 2 CO 3 ), has been demonstrated to prevent memory impairment and AChE activity in zebrafish induced by scopolamine (Zanandrea et al, 2018).…”

Transgenic fluorescent zebrafish lines that have revolutionized biomedical research

“…They inserted the E1b promoter into the flanking sites of the UAS promoter and then cloned human TAU-P301L and DsRed fluorescent protein gene in both directions of the UAS promoter in the pT2KXIGdeltaIN plasmid, resulting in construction of Tg(UAS-E1B:DsRed,Hsa.MAPT_P301L) plasmid, with which the cognate transgenic line was established using Tol2-mediated integration. This line was used to study a role for BDNF signaling in tauopathy [ 196 ], microglial dynamics against tauopathic neurons [ 197 ], and the mechanism by which pathological tau proteins aggregate [ 198 , 199 ].…”

Non-Rodent Genetic Animal Models for Studying Tauopathy: Review of Drosophila, Zebrafish, and C. elegans Models

“…For example, dysregulated signaling of brain-derived neurotrophic factor (BDNF) is strongly associated with neurodegenerative diseases [196], but how BDNF signaling affects tauopathy or vice versa remains unclear. By exploiting the human Tau P301L zebrafish model, it was shown that the BDNF level was reduced and associated with axonal developmental defects, but not neuronal death, in the tauopathy condition, since exogenous BDNF supplementation was able to rescue the primary axonal growth but had no effect on Tau-induced apoptotic cells [197]. In addition, HS3ST2 (heparan sulphate glucosamine 3-O-sulphotransferase 2), also known as 3OST2, and REG-1α (regenerating islet-derived 1α) are two new factors that were shown to be critical for the abnormal phosphorylation of Tau in the hTau P301L zebrafish model [198].…”