Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
Nat Neurosci. 2024 Oct;27(10):1918-1933. doi: 10.1038/s41593-024-01740-1. Epub 2024 Aug 26.
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 病的一个共同特征，其特征是神经元和神经胶质细胞中 Tau 的积累。神经元中的高 ROS 会导致脂质的产生和有毒过氧化物脂质 (LPO) 的输出。神经胶质细胞摄取这些 LPO 并将其纳入脂质滴 (LD) 中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 LD，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 是神经胶质细胞 LD 形成和抵抗神经元 LPO 的必需物质。同样，内源性 Tau 在大鼠星形胶质细胞和人少突胶质样细胞中对于 LD 的形成和 LPO 的分解代谢也是必需的。在行为上，缺乏神经胶质 Tau 的果蝇寿命缩短，运动缺陷可通过给予抗氧化剂 N-乙酰半胱氨酸酰胺得到挽救。总的来说，这项工作为 Tau 在减轻大脑中 ROS 方面在神经胶质细胞中的重要作用提供了新的见解。
