Duncan NRI Faculty and Staff Publications
Publication Date
10-1-2024
Journal
Nature Neuroscience
DOI
10.1038/s41593-024-01740-1
PMID
39187706
PMCID
PMC11809452
PubMedCentral® Posted Date
2-10-2025
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Animals, tau Proteins, Oxidative Stress, Neuroglia, Neurons, Lipid Droplets, Rats, Humans, Reactive Oxygen Species, Drosophila, Astrocytes, Coculture Techniques, Cells, Cultured
Abstract
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.