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<p>Astrocytes help protect neurons from potential damage caused by reactive oxygen species (ROS). While ROS can also exert beneficial effects, it remains unknown how neuronal ROS signalling is activated during memory formation, and whether astrocytes play a role in this process. Here we discover an astrocyte-to-neuron H<sub>2</sub>O<sub>2</sub> signalling cascade in <i>Drosophila</i> that is essential for long-term memory formation. Stimulation of astrocytes by acetylcholine induces an increase in intracellular calcium ions, which triggers the generation of extracellular superoxide (O<sub>2</sub>•<sup>–</sup>) by astrocytic NADPH oxidase. Astrocyte-secreted superoxide dismutase 3 (Sod3) converts O<sub>2</sub>•<sup>–</sup> to hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), which is imported into neurons of the olfactory memory centre, the mushroom body, as revealed by in vivo H<sub>2</sub>O<sub>2</sub> imaging. Notably, Sod3 activity requires copper ions, which are supplied by neuronal amyloid precursor protein. We also find that human amyloid-β peptide, implicated in Alzheimer’s disease, inhibits the nAChRα7 astrocytic cholinergic receptor and impairs memory formation by preventing H<sub>2</sub>O<sub>2</sub> synthesis. These findings may have important implications for understanding the aetiology of Alzheimer’s disease.</p>

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Astrocyte-to-neuron H2O2 signalling supports long-term memory formation in Drosophila and is impaired in an Alzheimer’s disease model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月24日

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  • Yasmine Rabah,
  • Jean-Paul Berwick,
  • Nisrine Sagar,
  • Laure Pasquer,
  • Pierre-Yves Plaçais,
  • Thomas Preat

摘要

Astrocytes help protect neurons from potential damage caused by reactive oxygen species (ROS). While ROS can also exert beneficial effects, it remains unknown how neuronal ROS signalling is activated during memory formation, and whether astrocytes play a role in this process. Here we discover an astrocyte-to-neuron H2O2 signalling cascade in Drosophila that is essential for long-term memory formation. Stimulation of astrocytes by acetylcholine induces an increase in intracellular calcium ions, which triggers the generation of extracellular superoxide (O2•–) by astrocytic NADPH oxidase. Astrocyte-secreted superoxide dismutase 3 (Sod3) converts O2•– to hydrogen peroxide (H2O2), which is imported into neurons of the olfactory memory centre, the mushroom body, as revealed by in vivo H2O2 imaging. Notably, Sod3 activity requires copper ions, which are supplied by neuronal amyloid precursor protein. We also find that human amyloid-β peptide, implicated in Alzheimer’s disease, inhibits the nAChRα7 astrocytic cholinergic receptor and impairs memory formation by preventing H2O2 synthesis. These findings may have important implications for understanding the aetiology of Alzheimer’s disease.