TauLUM, an in vivo Drosophila sensor of tau multimerization, identifies neuroprotective interventions in tauopathy

Abstract

Summary: 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 “tauLUM,” allows investigators to quantify tau multimerization at individual time points or longitudinally in adult, living animals housed in a 96-well plate. TauLUM 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 tauLUM flies, establishing the suitability of this system for future drug and genetic modifier screening. Overall, our studies position tauLUM as a powerful in vivo discovery platform that leverages the advantages of the Drosophila model organism to better understand tau multimerization. Motivation: Deposition of tau into fibrillar aggregates is a core feature of Alzheimer’s disease and related tauopathies. However, current systems to investigate tau multimerization are based on artificial cell culture systems or rely on analyses of postmortem rodent brain tissue. To overcome these limitations and elucidate the mechanisms that mediate tau multimerization, we present tauLUM, a luminescence-based Drosophila sensor of tau multimerization capable of longitudinal measurements in a living, aging brain.

Keywords

• tau
• Alzheimer’s disease
• neurodegeneration
• split-luciferase
• Drosophila