Department of Agricultural Sciences, University of Naples "Federico II", 80055 Portici, Italy.
CEINGE Biotecnologie Avanzate, 80145 Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", 80131 Naples, Italy.
Biochim Biophys Acta Proteins Proteom. 2020 Oct;1868(10):140471. doi: 10.1016/j.bbapap.2020.140471. Epub 2020 Jun 17.
Free d-aspartate is abundant in the mammalian embryonic brain. However, following the postnatal onset of the catabolic d-aspartate oxidase (DDO) activity, cerebral d-aspartate levels drastically decrease, remaining constantly low throughout life. d-Aspartate stimulates both glutamatergic NMDA receptors (NMDARs) and metabotropic Glu5 receptors. In rodents, short-term d-aspartate exposure increases spine density and synaptic plasticity, and improves cognition. Conversely, persistently high d-Asp levels produce NMDAR-dependent neurotoxic effects, leading to precocious neuroinflammation and cell death. These pieces of evidence highlight the dichotomous impact of d-aspartate signaling on NMDAR-dependent processes and, in turn, unveil a neuroprotective role for DDO in preventing the detrimental effects of excessive d-aspartate stimulation during aging. Here, we will focus on the in vivo influence of altered d-aspartate metabolism on the modulation of glutamatergic functions and its involvement in translational studies. Finally, preliminary data on the role of embryonic d-aspartate in the mouse brain will also be reviewed.
游离的 D-天冬氨酸在哺乳动物胚胎大脑中含量丰富。然而，在出生后，代谢性 D-天冬氨酸氧化酶（DDO）活性开始发挥作用，导致大脑中的 D-天冬氨酸水平急剧下降，并在整个生命过程中保持在较低水平。D-天冬氨酸能同时刺激谷氨酸能 NMDA 受体（NMDARs）和代谢型 Glu5 受体。在啮齿类动物中，短期暴露于 D-天冬氨酸可增加棘突密度和突触可塑性，并改善认知能力。相反，持续高水平的 D-天冬氨酸会产生 NMDAR 依赖性神经毒性作用，导致过早的神经炎症和细胞死亡。这些证据强调了 D-天冬氨酸信号对 NMDAR 依赖性过程的双重影响，并揭示了 DDO 在预防衰老过程中过量 D-天冬氨酸刺激的有害影响方面的神经保护作用。在这里，我们将重点关注体内改变 D-天冬氨酸代谢对谷氨酸能功能的调节作用及其在转化研究中的作用。最后，还将回顾胚胎 D-天冬氨酸在小鼠大脑中的作用的初步数据。
