Tauopathies are devastating neurodegenerative disorders characterized by Tau hyperphosphorylation, neurofibrillary tangle (NFT) formation, neuronal dysfunction, and cognitive decline. Here, we establish a new Drosophila tauopathy model expressing eGFP-tagged human TauWT or the disease-associated TauP301L variant in the nervous system. TauP301L expression recapitulates key pathological and behavioral hallmarks of tauopathy, including elevated Tau hyperphosphorylation, accumulation of NFT-like, pTau-positive assemblies in vivo, reduced lifespan, hyperactivity, sleep loss, progressive locomotor decline, and age-dependent brain degeneration. Strikingly, TauP301L also disrupts the architecture of the mushroom body, a learning- and memory-related circuit in Drosophila, revealing an early disruption of neural circuit formation that is distinct from adult neurodegenerative phenotypes. We further show that suppression of serotonin 5-HT7R-CDK5 signaling pathway, either by genetic knockdown or pharmacological inhibition with inverse agonist, rescues Tau-induced behavioral and anatomical phenotypes. These findings identify 5-HT7R signaling as a conserved and druggable modifier of Tau toxicity and establish this model as a powerful in vivo platform for mechanistic studies and therapeutic discovery in tauopathies.
Tsap, M. I., Navrotska, V. V., Labus, J., Ponimaskin, E., Yatsenko, A. S., Shcherbata, H. R.
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