Organization of the human and zebrafish MAPT genes. Human MAPT gene is represented with the major isoforms used in transgenic models and found in patients, 2N4R, 0N4R, and 0N3R. Orange exons encode N-terminal domain and green exons encode repeats domain (R) that belong to microtubule binding domains. Exon 10 is alternatively spliced to generate 3R isoform. Zebrafish mapta and maptb genes have 13 exons each (blue), with green exons encoding microtubule binding domains, and yellow one labelling alternatively spliced exons.

Transgenes used to generate stable lines. (1) Human MAPT 4R isoform is expressed under Eno2 promoter [29]. (2) Double transgenic line using Gal4/UAS system: Gal4 is expressed under HuC promoter and bind to bidirectional UAS promoter to induced the expression in the same neuron of DsRed and hTauP301L proteins [30]. (3) Using HuC promoter driving Gal4 line cross with UAS-driven fused Dendra:MAPT or Dendra:MAPTA152T results in neuronal expression of human proteins Dendra-hTauWT or Dendra-hTauAT52T [31]. (4) Conditional transgene using CreERT2_LoxP recombination: tamoxifen incubation results in expression of 2 proteins: EGFP and hTauP301L in her4.1 positive neural stem cells [32]. (5) Retina expression of MAPT or MAPTP301L driven by rhodopsin (Rho) promoter [33,34].

Phenotype evolution during zebrafish development for the hTauP301L mutation. NFT: neurofibrillary tangles; VMR: visual motor response, ASR: acoustic startle response.

Summary of the main strategies and findings in Tauopathy zebrafish models. Upon hyperphosphorylation, Tau protein detached from the microtubules and form oligomers. Oligomer accumulation led to pre-tangles and in some cases to neurofibrillary tangles. Zebrafish transgenic lines overexpressed human Tau proteins in neurons which led to apoptosis (green cells), inflammation response with microglia activation (red cells) and locomotion defects (visual motor response profile). Transgenic lines for human Tau WT or P301L and A152T mutations, revealed that neuroprotective factors can rescue neurotoxicity as well as activation of the proteasome and autophagy pathways.