The role of glia-neuronal lactate shuttle in brain aging

年龄相关记忆损害(AMI)是大脑老化的衰弱结果，是由果蝇体内与年龄相关的线粒体变性酶丙酮酸羧基酶(PC)的增加引起的。由于PC的增加可能会抑制神经元源性能量来源乳酸的合成，在本研究中，我们试图证明PC活性的增加会抑制胶质细胞-神经元乳酸穿梭(GNLS)，从而损害记忆的形成。然而，我们的行为和生化数据表明，PC依赖的记忆缺陷不是由GNLS抑制引起的。虽然PC活性的增加并不抑制GNLS，但它可能通过增加其强大的抑制剂草酰乙酸酯(OAA)和天冬氨酸(Asp)的生物合成来抑制丝氨酸消旋酶(SR)。SR将L-丝氨酸转化为D-丝氨酸，D-丝氨酸是一种胶质细胞来源的N-甲基-D-天冬氨酸受体激动剂。正如我们预期的那样，D-丝氨酸/L-丝氨酸比率在老年急性心肌梗死患者中显著降低，并且这种降低被DPC突变所抑制。此外，通过喂食果蝇D-丝氨酸，可以改善急性心肌梗死和由胶质细胞过度表达PC引起的记忆障碍。我们认为，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 and caused by age-related increase in pyruvate carboxylase (PC), a mitochondrial anaplerotic enzyme, in Drosophila. As increase in PC may suppress synthesis of lactate, glia-derived energy source for neurons, in this study, we tried to demonstrate that increase in PC activity inhibits glia-neuron lactate shuttle (GNLS) thereby impairs memory formation. However, our behavioral and biochemical data demonstrated that PC-dependent memory defects are not caused by GNLS inhibition. Although increase in PC activity does not inhibit GNLS, it may inhibit serine racemase (SR) via increasing biosynthesis of its potent inhibitors oxaloacetate (OAA) and aspartate (Asp). SR converts L-serine to D-serine, a glia-derived NMDA receptor agonist. As we expected, D-serine/L-serine ratio is significantly decreased in aged AMI-suffered flies, and this decrease is suppressed by dPC mutations. Furthermore, both AMI and memory defects caused by overexpressing PC in glia are ameliorated by feeding flies D-serine. We propose that age-related increases in glial mitochondrial dPC activity cause AMI by reducing D-serine production.