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.

活性氧 （ROS） 的积累是 tau 蛋白病的常见特征，其定义是 Tau 蛋白在神经元和神经胶质细胞中的积累。神经元中的高 ROS 会导致脂质产生和有毒过氧化物脂质 （LPO） 的出口。神经胶质细胞吸收这些 LPO 并将其掺入脂滴 （LD） 中以进行储存和分解代谢。我们发现，在神经胶质细胞中过表达 Tau 会破坏果蝇和大鼠神经元-星形胶质细胞共培养物中的 LDs，使神经胶质细胞对有毒的神经元 LPO 敏感。使用新的果蝇 tau 功能丧失等位基因和 RNA 介导的干扰，我们发现内源性 Tau 是神经胶质 LD 形成和保护神经元 LPO 所必需的。同样，大鼠星形胶质细胞和人少突胶质细胞样细胞需要内源性 Tau 来形成 LD 和 LPO 分解。从行为上讲，缺乏神经胶质细胞 Tau 的果蝇寿命缩短和运动缺陷，这些缺陷可以通过施用抗氧化剂 N-乙酰半胱氨酸酰胺来补救。总体而言，这项工作提供了对 Tau 在神经胶质细胞中减轻大脑 ROS 的重要作用的见解。