Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
PLoS One. 2012;7(10):e44933. doi: 10.1371/journal.pone.0044933. Epub 2012 Oct 11.
Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme for nicotinamide adenine dinucleotide (NAD) biosynthesis, and can be found either intracellularly (iNAMPT) or extracellularly (eNAMPT). Studies have shown that both iNAMPT and eNAMPT are implicated in aging and age-related diseases/disorders in the peripheral system. However, their functional roles in aged brain remain to be established. Here we showed that upon aging, NAMPT level increased in serum but decreased in brain, decreased in cortex and hippocampus but remained unchanged in cerebellum and striatum in brain, and increased in microglia but likely decreased in neuron. Accordingly, total NAD (tNAD) level significantly decreased in hippocampus, cerebellum and striatum in aged brain. Application of recombinant NAMPT, mimicking the elevated serum NAMPT level, enhanced the susceptibility of cerebral endothelial cells to ischemic injury, while inhibition of iNAMPT by FK866, a specific inhibitor, reduced intracellular NAD level and induced neuronal death. Taken together, we have revealed a region- and cell-specific change of NAMPT level in brain and serum upon aging, deduced its potential consequences, which suggests that NAMPT is a regulatory factor in aging and age-related brain diseases.
烟酰胺磷酸核糖转移酶（NAMPT）是烟酰胺腺嘌呤二核苷酸（NAD）生物合成的关键酶，可存在于细胞内（iNAMPT）或细胞外（eNAMPT）。研究表明，iNAMPT 和 eNAMPT 都与外周系统的衰老和与年龄相关的疾病/障碍有关。然而，它们在衰老大脑中的功能作用仍有待确定。在这里，我们发现随着年龄的增长，NAMPT 水平在血清中增加，但在大脑中减少，在大脑皮层和海马体中减少，但在小脑和纹状体中不变，在小胶质细胞中增加，但在神经元中可能减少。相应地，衰老大脑中海马体、小脑和纹状体中的总 NAD（tNAD）水平显著降低。应用重组 NAMPT，模拟血清中升高的 NAMPT 水平，增强了大脑内皮细胞对缺血性损伤的易感性，而特异性抑制剂 FK866 抑制 iNAMPT 则降低了细胞内 NAD 水平并诱导神经元死亡。总之，我们揭示了衰老时大脑和血清中 NAMPT 水平的区域和细胞特异性变化，推断了其潜在的后果，这表明 NAMPT 是衰老和与年龄相关的大脑疾病的调节因子。
