Tau, an 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 split-luciferase-based sensor of tau-tau interaction. This model, which we term "tau," allows investigators to quantify tau multimerization at individual time points or longitudinally in adult, living animals housed in a 96-well plate. Tau causes cell death in the adult 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 flies, establishing the suitability of this system for future drug and genetic modifier screening. Overall, our studies position tau as a powerful discovery platform that leverages the advantages of the model organism to better understand tau multimerization.