Human TAU overexpression results in TAU hyperphosphorylation without neurofibrillary tangles in adult zebrafish brain.

Microtubule-associated TAU protein is a pathological hallmark in Alzheimer's disease (AD), where hyperphosphorylation of TAU generates neurofibrillary tangles. To investigate the effects of TAU in a regenerative adult vertebrate brain system, we generated a cre/lox-based transgenic model of zebrafish that chronically expresses human TAU, which is a variant of human TAU protein that forms neurofibrillary tangles in mouse models and humans. Interestingly, we found that although chronic and abundant expression of TAU starting from early embryonic development led to hyperphosphorylation, TAU did not form oligomers and neurofibrillary tangles, and did not cause elevated apoptosis and microglial activation, which are classical symptoms of tauopathies in mammals. Additionally, TAU neither increased neural stem cell proliferation nor activated the expression of regenerative factor Interleukin-4, indicating that TAU toxicity is prevented in the adult zebrafish brain. By combining TAU expression with our established Aβ42 toxicity model, we found that Aβ42 ceases to initiate neurofibrillary tangle formation by TAU, and TAU does not exacerbate the toxicity of Aβ42. Therefore, our results propose a cellular mechanism that protects the adult zebrafish brain against tauopathies, and our model can be used to understand how TAU toxicity can be prevented in humans.