Tau(LUM), an in vivo Drosophila sensor of tau multimerization, identifies neuroprotective interventions in tauopathy

Tau protein aggregates are a defining neuropathological feature of “tauopathies,” a group of neurodegenerative disorders that include Alzheimer’s disease. In the current study, we develop a Drosophila split-luciferase-based sensor of tau-tau interaction. This model, which we term “tau(LUM),” allows investigators to quantify tau multimerization at individual time points or longitudinally in adult, living animals housed in a 96-well plate. Tau(LUM) causes cell death in the adult Drosophila brain and responds to both pharmacological and genetic interventions. We find that transgenic expression of an anti-tau intrabody or pharmacological inhibition of HSP90 reduces tau multimerization and cell death in tau(LUM) flies, establishing the suitability of this system for future drug and genetic modifier screening. Overall, our studies position tau(LUM) as a powerful in vivo discovery platform that leverages the advantages of the Drosophila model organism to better understand tau multimerization.