A novel signaling pathway that regulates brain aging

年龄相关记忆损伤(AMI)是大脑老化的一种衰弱结果，可以通过降低PKA活性来抑制果蝇的这种现象。然而，急性心肌梗死的分子机制仍不清楚。利用野生型和PKA突变体的蛋白质组学分析，我们发现了与急性心肌梗死相关的果蝇丙酮酸羧基酶(DPC)活性的增加，DPC是一种线粒体变性酶。遗传和生化数据表明，与年龄相关的胶质DPC增加会导致急性心肌梗死，而PKA突变通过降低DPC活性来抑制急性心肌梗死。虽然氧化应激增加被认为是引起急性心肌梗死的原因，但DPC活性的增加与氧化应激的增加无关。值得注意的是，尽管胶质细胞来源的NMDA受体激动剂D-丝氨酸的产量在老年果蝇中减少，但这种减少被DPC突变所抑制，急性心肌梗死也通过喂食D-丝氨酸而得到改善。我们提出了一种新的氧化应激非依赖性的急性心肌梗死信号通路，其中与年龄相关的胶质线粒体DPC活性的增加通过减少D-丝氨酸的产生而导致急性心肌梗死。

Age-related memory impairment(AMI) is a debilitating consequence of brain aging that can be suppressed in Drosophila by reducing PKA activity. However, the molecular mechanisms underlying AMI remain unclear. Using proteome analyses of wild-type and PKA mutants, we identified an AMI-associated increase in the activity of Drosophila pyruvate carboxylase(dPC), a mitochondrial anaplerotic enzyme. Genetic and biochemical data demonstrate that age-related increases in glial dPC cause AMI and that PKA mutations suppress AMI by reducing dPC activity. Although increased oxidative stress has been proposed to cause AMI, increases in dPC activity are not associated with increased oxidative stress. Strikingly, although the production of D-serine, a glia-derived NMDA receptor agonist, decreases in aged flies, this decrease is suppressed by dPC mutations and AMI is ameliorated by feeding flies D-serine. We propose a novel oxidative stress-independent AMI signaling pathway in which age-related increases in glial mitochondrial dPC activity cause AMI by reducing D-serine production.