The role of glia-neuronal lactate shuttle in brain aging

果蝇的线粒体回补酶丙酮酸羧化酶（PC）的活性随年龄增长而增加，从而导致大脑衰老导致的记忆障碍（AMI）。由于PC的增加可能抑制神经元的神经胶质源性能量来源乳酸的合成，在本研究中，我们试图证明PC活性的增加抑制神经胶质-神经元乳酸穿梭（GNLS），从而损害记忆形成。然而，我们的行为和生化数据表明，PC依赖性记忆缺陷不是由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有效抑制剂草酰乙酸（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-丝氨酸是一种神经胶质衍生的NMDA受体激动剂。正如我们所预期的，D-丝氨酸/L-丝氨酸比率在老年AMI患者中显著降低，并且这种降低被dPC突变抑制。此外，AMI和记忆缺陷所造成的过度表达的PC在胶质细胞改善喂养苍蝇D-丝氨酸。我们认为年龄相关的神经胶质线粒体dPC活性增加通过减少D-丝氨酸的产生引起AMI。

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.