Nicotinamide phosphoribosyltransferase may be involved in age-related brain diseases.
Nicotinamide phosphoribosyltransferase may be involved in age-related brain diseases.
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DOI：
10.1371/journal.pone.0044933
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Zhang WP
中科院分区：
文献类型：
--
作者：
Liu LY;Wang F;Zhang XY;Huang P;Lu YB;Wei EQ;Zhang WP
烟酰胺磷酸核糖基转移酶 (NAMPT) 是烟酰胺腺嘌呤二核苷酸 (NAD) 生物合成的关键酶，可以在细胞内 (iNAMPT) 或细胞外 (eNAMPT) 发现。研究表明，iNAMPT 和 eNAMPT 都与衰老和与年龄相关的外周系统疾病/紊乱有关。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，但在大脑中降低，在皮质和海马中降低，但在小脑和纹状体中保持不变，在小胶质细胞中增加，但在神经元中可能降低。因此，老年大脑海马体、小脑和纹状体中的总 NAD (tNAD) 水平显着下降。应用重组NAMPT模拟升高的血清NAMPT水平，增强脑内皮细胞对缺血性损伤的敏感性，而特异性抑制剂FK866抑制iNAMPT，降低细胞内NAD水平并诱导神经元死亡。综上所述，我们揭示了衰老过程中大脑和血清中 NAMPT 水平的区域和细胞特异性变化，并推断出其潜在后果，这表明 NAMPT 是衰老和与年龄相关的脑疾病的调节因素。
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.
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