Context-dependent toxicity of human Tau isoforms in a Drosophila tauopathy model

Tauopathies are characterised by progressive deterioration of brain regions due to abnormal accumulation of microtubule-associated protein tau (MAPT). Alternative splicing of MAPT pre-mRNA produces six isoforms, classified as 3R or 4R depending on whether they contain three or four microtubule-binding repeats. Although many tauopathies are 3R- or 4R-specific, individual isoform contributions to neurotoxicity remain unclear. To investigate isoform-specific toxicity, we generated Drosophila lines with transgenes encoding each human tau (hTau) isoform inserted at the same locus. In young adults, hTau abundance did not differ significantly among lines, yet expression levels were sufficient to induce visible, isoform-specific phenotypes. Across assays, hTau toxicity depended on expression window, tissue type, and neuronal identity; 4R isoforms were generally more toxic than 3R, but individual isoform effects differed by context. In selected neuronal populations, neurons classed as vulnerable showed early degeneration and continued decline, whereas resilient neurons degenerated only at the later time point. This suggests that, in some neurons, resilience may reflect early resistance to disease processes that is lost with age and exposure to age-related stressors. These phenotypes were not readily explained by hTau abundance or AT8-positive hTau. Together, we show that tau toxicity emerges from interactions between isoform-specific properties and cellular environment.