Tau is required for glial lipid droplet formation and resistance to neuronal oxidative stress

The accumulation of reactive oxygen species (ROS) is a common feature of tauopathies, defined by Tau accumulations in neurons and glia. High ROS in neurons causes lipid production and the export of toxic peroxidated lipids (LPOs). Glia uptake these LPOs and incorporate them into lipid droplets (LDs) for storage and catabolism. We found that overexpressing Tau in glia disrupts LDs in flies and rat neuron–astrocyte co-cultures, sensitizing the glia to toxic, neuronal LPOs. Using a new fly tau loss-of-function allele and RNA-mediated interference, we found that endogenous Tau is required for glial LD formation and protection against neuronal LPOs. Similarly, endogenous Tau is required in rat astrocytes and human oligodendrocyte-like cells for LD formation and the breakdown of LPOs. Behaviorally, flies lacking glial Tau have decreased lifespans and motor defects that are rescuable by administering the antioxidant N -acetylcysteine amide. Overall, this work provides insights into the important role that Tau has in glia to mitigate ROS in the brain. Goodman et al. found that Tau is critical for ROS-induced lipid droplet formation in glia from flies and mammals. Too much or too little glial Tau disrupts lipid droplets, leaving the glia susceptible to neuronal ROS-induced damage and causing phenotypes in tau −/− flies.